User:Ramiro Barrantes/FpgNeiRepair

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= The FpgNei Protein Superfamily =
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__NOTOC__
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== Background on DNA Repair==
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= The FpgNei Protein Family =
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The genome of any living organisms is being continuously affected by exogenous and endogenous agents, such as ultraviolet light, ionizing radiation, different chemicals and the cell's own metabolites (such as reactive oxygen). Therefore, different systems have evolved to repair these damages, with some of these systems shared throughout all lifeforms. Therefore, the proper functioning of DNA repair is critical for survival. There are six pathways of DNA repair (reviewed in Friedberg et al), and one of them is base-excision repair. The latter's distinguishing feature is that it removes lesions as single bases, as opposed to dNMPs or short oligonucleotides like other systems. <ref>PMID: 18259689</ref>
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Base excision repair's signature enzyme are the DNA glycosylases. These enzymes work by recognizing and removing a single damaged base from DNA. They are called DNA glycosylases because they hydrolize the N-glycosidic bond of the damaged deoxynucleoside. The subsequent steps of the pathway (strand incision, gap-filling and ligation) are done by other enzymes. <ref>PMID: 18259689</ref><ref>PMID:19153658</ref>
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[[#Background on DNA Repair|1. Background on DNA Repair]] <br>
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[[#Background on Fpg/Nei|2. Background on Fpg/Nei]]<br>
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[[#Overall Function and Structure|2.1 Overall Function and Structure]]<br>
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[[#Latent Structural Characters (LSCs)|3. Latent Structural Characters Summary]]<br>
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[[#References|5. References]]
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== Background on Fpg Nei ==
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==Background on DNA Repair==
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[[Image:Picture 9.png|thumb|166px|left|Cartoon phylogenetic tree of the FpgNei protein family. Note that this phylogeny can be appreciated in two levels: by the distribution and number of FpgNei subfamilies in different organisms; and by the kinds of damages that can be repaired]]
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The genome of any living organism is continuously affected by exogenous and endogenous agents, such as ultraviolet light, ionizing radiation, different chemicals and the cell's own metabolites (such as reactive oxygen). Therefore, different systems have evolved to repair these damages, with some of these systems shared throughout all lifeforms. Therefore, the proper functioning of DNA repair is critical for survival. There are six pathways of DNA repair (reviewed in Friedberg et al), which include base-excision repair. The latter's distinguishing feature is that it removes lesions as single bases, as opposed to dNMPs or short oligonucleotides like other systems. <ref>PMID:18259689</ref>
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== Overall Function and Structure ==
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Base excision repair's signature enzyme are the DNA glycosylases. These enzymes work by recognizing a damaged base, and then hydrolizing the N-glycosidic bond of the damaged deoxynucleoside and thus removing a single damaged base from DNA. The subsequent steps of the pathway (strand incision, gap-filling and ligation) are done by other enzymes. <ref>PMID: 18259689</ref><ref>PMID:19153658</ref>
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{| valign="top"
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| (For FPG, the structure used was [[1r2y]] and for Nei [[1k3w]]) Members of this family have <scene name='User:Ramiro_Barrantes/Workbench/Econeicoloreddomains/2' target="function"> two domains connected by a hinge region </scene>. DNA binds in a cleft between the domains. If EcoNei (structure [[1k3w]], <scene name='User:Ramiro_Barrantes/Workbench/Econeiorientationandkinking/2' target="function">E2,K52,N168 and R252 provide orientation and kinking to the DNA,</scene>, and <scene name='User:Ramiro_Barrantes/Workbench/Econeistabilizingsites/1' target="function">P1, E5 and R212 and others stabilize the damaged base </scene>(Thymine Glycol in the case of Nei). <ref>PMID:11847126</ref>. Some of these amino acids are stabilized by a <scene name='User:Ramiro_Barrantes/Workbench/Econeizincfinger/1' target="function"> Zinc Finger </scene> (although a zincless finger motif is present in some of these subfamilies <ref>PMID:15232006</ref>). Other key components are the intercalation loop (different between <scene name='User:Ramiro_Barrantes/Workbench/Fpgintercalationloop/1' target="function">Fpg</scene> and <scene name='User:Ramiro_Barrantes/Workbench/Econeiintercalationloop/2'>''E. coli Nei''</scene>), a group of amino acids that insert into the vacated spot left by the "flipped" base; and amino acids which contact the opposite strand and confer opposite-base specificity. Note that the last two elements discussed, the zinc vs. zincless finger, and the two kinds of intercalation loops, are examples of coevolving functional clusters, groups of amino acids that perform a function, and that might be unnecessary or compensated for within the other subfamilies. We developed a novel method for identifying these clusters and have applied it to bring insight into the structure, function and evolution FpgNei family.
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Several authors have suggested mechanisms for these enzymes, please see references for more information <ref>PMID:11847126</ref><ref>PMID:10921868</ref><ref>PMID:16243784</ref><ref>PMID:11912217</ref>.
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==Background on Fpg Nei==
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Homologous structures have been solved, including Fpg protein from Lactococcus Lactis ([[1pjj]])<ref>PMID: 16243784</ref>, Bacillus Stereothermophilus ([[1r2y]])<ref>PMID:14525999</ref>, Thermos Thermophilus ([[1ee8]])<ref>PMID:10921868</ref> and Escherichia Coli([[1k82]])<ref>PMID:11912217</ref> and Nei from Escherichia Coli ([[1k3w]])<ref>PMID:11847126</ref>. The overall structure is similar, and some of the damages include 8-oxoguanine and fapyG ([[1xc8]])<ref>PMID:15249553</ref>.
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==Overall Function and Structure==
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{| valign="top"
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| <applet load='1K3W' size='500' frame='true' align='left' caption='See structure column for structure reference' name="function" scene='User:Ramiro_Barrantes/Workbench/Econeiwater/1' />
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| valign="top"|(For FPG, the structure used was [[1r2y]] and for Nei [[1k3w]]) Members of this family have <scene name='User:Ramiro_Barrantes/Workbench/Gstfpglabeleddomains/4' target="function"> two domains (blue and orange) connected by a hinge region (purple). DNA (gray) binds in a cleft between the domains. </scene>. When enzyme binds to DNA, the damaged base
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|}
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== Latent Structural Characters (LSCs) ==
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We define a functional cluster as neighboring amino acids which have changed in rate or constraint for a given clade or set of clades. For example, the cysteines in the zinc finger are all conserved in the fpg1, fpg2, actinobacterial and eukaryotic clades, but have a higher rate in plants and neil1, as the latter have a zinc-less finger ([[#Functional Cluster: Zinc/zincless finger|see here for more information]]). We developed a novel method to find these groups of amino acids, discovering previously unknown groups of amino acids which be functionally important in some of these subfamilies.
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The table below has some of our main findings, there are two variants for each functional cluster in case that for one functional cluster there is a compensating cluster in the other subfamilies. If you click on one of them you will see the result in the structure, and you can go to the explanation and the sequence distribution below (we have found it helpful to open a separate screen to go along the structure).
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{| - style="font-size:18px;align=center"
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| <applet load='1R2Y' size='500' frame='true' align='left' name="fpg" scene='User:Ramiro_Barrantes/Workbench/Gstfpg/5'/>
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| <applet load='1K3W' size='500' frame='true' align='right' structure' name="ecoNei" scene='User:Ramiro_Barrantes/Workbench/Econeiwater/1' />
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|}
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<scene name='User:Ramiro_Barrantes/Workbench/Evertedbaseonbstfpg/1' target="function"> is everted</scene>, with <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgintercalationloop/2' target="function"> several residues intercalating in its place</scene>. This superfamily is also characterized by containing a <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgh2th/2' target="function">helix-two-turn-helix motif (H2TH, in purple) which contacts DNA via Asn174 (in yellow)</scene>; as well as a
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<scene name='User:Ramiro_Barrantes/Workbench/Gstfpgzincfinger/5' target="function"> zinc finger, which contacts DNA via Arg264 </scene>. Both the H2TH motif and the Zinc finger, as well as other residues
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<scene name='User:Ramiro_Barrantes/Workbench/Gstfpgdamagestabilizers/1' target="function"> stabilize the damaged base </scene>. <ref>PMID:11912217</ref>. Catalysis is believed to be mediated by <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgcatalyticresidues/3' target="function">P2, E3, E6 and R264</scene>. For information on the mechanism please consult <ref>PMID:16243784</ref><ref>PMID:11847126</ref><ref>PMID:15249553</ref><ref>PMID:11912217</ref><ref>PMID:10921868</ref>.
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Similarly In EcoNei (structure [[1k3w]], <scene name='User:Ramiro_Barrantes/Workbench/Econeiorientationandkinking/4' target="function">E2,K52,N168 and R252 provide orientation and kinking to the DNA,</scene>, and <scene name='User:Ramiro_Barrantes/Workbench/Econeistabilizingsites/2' target="function">P1, E5 and R212 and others stabilize the damaged base </scene>(Thymine Glycol in the case of Nei). <ref>PMID:11847126</ref>. Some of these amino acids are stabilized by [a <scene name='User:Ramiro_Barrantes/Workbench/Econeizincfinger/1' target="function"> Zinc Finger </scene> (although a zincless finger motif is present in some of these subfamilies <ref>PMID:15232006</ref>). Analogously to Fpg, <scene name='User:Ramiro_Barrantes/Workbench/Econeiintercalationloop/4'>''E. coli Nei'' residues insert into the vacated spot left by the "flipped" base</scene>), Note that the last two elements discussed, the zinc vs. zincless finger, and the two kinds of intercalation loops, are examples of coevolving functional clusters, groups of amino acids that perform a function, and that might be unnecessary or compensated for within the other subfamilies. We developed a novel method for identifying these clusters and have applied it to bring insight into the structure, function and evolution FpgNei family.
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| <applet load='1K3W' size='500' frame='true' align='left' caption='See structure column for structure reference' name="function" scene='User:Ramiro_Barrantes/Workbench/Gstfpglabeleddomains/3' />
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|-
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| valign="top"|===Phylogeny=== [[Image:Picture 9.png|thumb|400px|left|Cartoon phylogenetic tree of the FpgNei protein family. Note that this phylogeny can be appreciated in two levels: by the distribution and number of FpgNei subfamilies in different organisms; and by the kinds of damages that can be repaired (see table on the right)]]
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| valign="top"|===Table of preferred substrates===
{| class="wikitable" style="text-align:center"
{| class="wikitable" style="text-align:center"
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! Functional Cluster !! Variant 1 !! Variant 2 !! Fpg1 !! Fpg2 !! Plant !! Neil1 !! Neil2 !! Neil3 !! Proteo !! Actino1 !! Actino2 !! MimiVirus
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! Clade !! Function !! References
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| Support for perfectly conserved Asn174
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| Fpg || 8oxoG, Fapy-A, Fapy-G,Me-Fapy-G,Sp,Gh || <ref>PMID:11101315</ref><ref>PMID:11848931</ref>
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| <scene name='User:Ramiro_Barrantes/Workbench/Lys160asp178/6' target="fpg">Lys160 and Asp178</scene>
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| <scene name='User:Ramiro_Barrantes/Workbench/Econeiarginine171/4' target="ecoNei">Arg171</scene>
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| Y || Y || N || N || N || N || N || N || N || N
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|-
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| Stability of catalytic helix
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| EcoNei || Oxidized pyrimidines || <ref>PMID:9405426</ref>
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| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgglu8arg57leu4triad/3' target="fpg">Leu4,Glu8,Arg57</scene>
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| <scene name='User:Ramiro_Barrantes/Workbench/Econeisupporttriadcounterpart/1' target="ecoNei">Different</scene>
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| Y || Y || Y || N || N || N || N || N || N || N
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|-
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| Intercalation loop
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| Actinomycetes Nei1 || DHU || <ref>PMID:18457574</ref>
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| <scene name='User:Ramiro_Barrantes/Workbench/Fpgintercalationloop/2' target="fpg">D110,F108,R113,R112,F114</scene>
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| <scene name='User:Ramiro_Barrantes/Workbench/Econeiintercalationloop/3' target="ecoNei">Gln76,Met77,Tyr78</scene>
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| Y || Y || Y || N || N || N || N || N || N || Y
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|-
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| [[#Functional Cluster: Zinc/zincless finger|Zinc Finger]]
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| Actinomycetes Nei2 || ? ||
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| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgzincfinger/4' target="fpg">Zinc finger</scene>
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| <scene name='User:Ramiro_Barrantes/Workbench/Neil1zinclessfinger/3' target="ecoNei">Neil1 zincless finger</scene>
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| Y || Y || N || N || Y || Y || Y || Y || Y || N
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|-
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| Recognition complex
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| Fpg2 || ? ||
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| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgrecognitioncomplex/1' target="fpg">Loop from Gly218 to Gly233</scene>
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| none
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| Y || N || N || N || N || N || N || N || N || N
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|-
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| Neil1-specific: Support for Lys60
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| Plant&Fungi || Sp,Gh || <ref>PMID:19217358</ref>
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| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgneil1covariate/3' target="fpg">E137,R58,G135,L134</scene>
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| <scene name='User:Ramiro_Barrantes/Workbench/Neil1lys60support/2' target="ecoNei">Covariation with Asn172</scene>
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| Y || Y || Y || N || Y || Y || Y || Y || Y || Y
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|-
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| PlantFungi-specific: R254 DNA binding
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| Neil1 || Sp,Gh,on double&single strand DNA, Both stereoisomers of Tg|| <ref>PMID:15533836</ref><ref>PMID:12713815</ref>
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| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgtyr243/1' target="fpg">Y242,G243,R244</scene>
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|-
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| different in plants
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| Neil2 || Sp,Gh,on double&single stranded DNA || <ref>PMID:15533836</ref>
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| Y || Y || N || Y || Y || Y || N || Y || Y || Y
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|-
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| Neil3 || not clear || <ref>PMID:19170771</ref>
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|}
|}
|}
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<table><tr valign="top"><td>
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===Mechanisms===
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=== LSC1: Stability of perfectly conserved Asn168 ===
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Several authors have suggested mechanisms for these enzymes, please see references for more information <ref>PMID:11847126</ref><ref>PMID:10921868</ref><ref>PMID:16243784</ref><ref>PMID:11912217</ref>.
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<p>[[Image:F1WebLogo.jpg|thumb|166px|left|WebLogo for the first functional unit, note the covariation between lysine nad arginine, which hydrogen-bond with the crucial Asn174]] (<scene name='User:Ramiro_Barrantes/Workbench/Lys160asp178/6' target="fpg"> Click here to watch this cluster in Geobacillus Fpg: present in Fpg1, Fpg2 and Plants and Fungi</scene> and <scene name='User:Ramiro_Barrantes/Workbench/Econeiarginine171/4' target="ecoNei"> here for the compensating one in E. Coli: present in Actinobacteria 1 and 2, Proteacteria and all vertebrate subfamilies </scene>). Asn174, along with two other amino acids have an effect in the orientation and kinking of the DNA <ref>PMID:11847126</ref>, keeping the proper arrangement between the zinc finger and the H2TH <ref>PMID:10921868</ref>. In 4 of the 9 clades (Fpg1, Fpg2 and Plants and Fungi) Asn174 is supported by the amino acid corresponding to Lys160, which in turn hydrogen bonds with Leu249 and Ser250. In the other clades (Actinobacteria 1 and 2, Proteacteria and all vertebrate subfamilies), this role is played by Arg171, which originates on a different helix. The Zinc Finger is shaped differently in the absence of DNA, and there is a hydrogen bond between one of the beta-sheets and the arginine. Site directed mutagenesis has been performed on both Lys155 (corresponding lysine in E. coli Fpg) and as well as Arg171, with the first one being associated with premature dissociation and loss of activity and the latter with significant loss of activity <ref>PMID:11554299</ref><ref>PMID:17002303</ref>.</p>
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</td>
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<td>
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=== LSC2: Stability of catalytic helix ===
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(<scene name='User:Ramiro_Barrantes/Workbench/Gstfpgglu8arg57leu4triad/3' target="fpg"> Click here to watch this cluster in Geobacillus Fpg: present in Fpg1, Fpg2, Plants and Fungi</scene> and <scene name='User:Ramiro_Barrantes/Workbench/Econeisupporttriadcounterpart/1' target="ecoNei"> here for how this region looks in ''E. coli'': present in Actinobacteria 1 and 2, Proteobacteria and all vertebrate subfamilies </scene>)
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<p>[[Image:F2WebLogo.jpg|thumb|166px|left|The LER triad interact in stabilize the catalytic helix (which includes Pro2 and Glu3 and Glu6), it is not clear how this is achieved in the other subfamilies]] The triad Leu4, Glu8 and Arg57 interact and provide stability to helixA, which has the catalytic residue Pro2,Glu3 and Glu6 <ref>PMID:16243784</ref><ref>PMID:10921868</ref>. This triad is present in the same four clades as above (Fpg1, Fpg2 and Plants and Fungi) but absent in the remaining clades and it is not clear how the same stability is provided. Leu211 also has a hydrophobic interaction with Leu4. The role of Gly4 is not known</p>
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</td>
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<tr valign="top"><td>
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=== LSC3: Stability of intercalation loop ===
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<scene name='User:Ramiro_Barrantes/Workbench/Fpgintercalationloop/2' target="fpg">Click here for intercalation loop in Fpg1, Fpg2 Plants and Fungi and Neil1</scene> and <scene name='User:Ramiro_Barrantes/Workbench/Econeiintercalationloop/3' target="ecoNei">here for corresponding structure in ''E. coli'' Nei</scene>)
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<p>[[Image:IntercalationLoop.jpg|thumb|166px|right|The residue in positions 77 and 78 suggest a possible intercalation loop]][[Image:IntercalationLoopSupport.jpg|thumb|166px|right|This structure provides stability for the amino acids that insert into the space vacated by the damaged base]] The intercalation loop inserts into the space left by the excised base. This structure, as well as a group of amino acids that support it exhibit high conservation in Fpg, AY, plants and Neil1, and the others have a something different. The best studied example of its counterpart is in ''E. coli'' Nei, which fulfills the same purpose <ref>PMID:17002303</ref>.
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The residue E2 and E6 have been mutated, with the first one inactivating the protein and the second one having no major effect <ref>PMID:11711552</ref>. The intercalation loop inserts into the DNA when the base is everted. Note that the amino acid composition suggests that mimivirus has this structure.</p>
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</td><td>
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=== LSC4: Stability of key Gly59 and Lys60 ===
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<p>[[Image:Lys60Stability.jpg|thumb|166px|right|Notice the covariation in Neil1 and the rest with positions 134 and 137 and 170]](<scene name='User:Ramiro_Barrantes/Workbench/Gstfpgneil1covariate/3' target="fpg">Click here to look at network of sites stabilizing key residue Lysine 60</scene> and <scene name='User:Ramiro_Barrantes/Workbench/Neil1lys60support/2' target="ecoNei"> here for the compensating network in Neil1, mainly Asn172</scene>) Gly59 and Lys60 are important in the activity of MutM <ref>PMID:9826758</ref><ref>PMID:11847126</ref>. We hypothesize that Glu137 is very important to maintain its stability, this amino acid is compensated for by Asn172 in Neil1</p>
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</td>
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<tr valign="top"><td>
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=== LSC8: DNA binding Tyrosine ===
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<p>[[Image:PlantSpecific.jpg|thumb|166px|right|Tyrosine that binds to DNA, the plant has a different structure alltogether]] </p>
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</td><td>
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=== LSC6: Zinc/zincless finger ===
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===Solved Structures===
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<p>[[Image:ZincFinger.jpg|thumb|166px|right|The Zinc Finger helps as a support of the key R264 residue]]<scene name='User:Ramiro_Barrantes/Workbench/Gstfpgzincfinger/4' target="fpg"> Click here to see the Zinc finger on Bst Fpg, note the 4 cysteines. The zinc finger is key for DNA binding </scene>
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Homologous structures have been solved, including Fpg protein from Lactococcus Lactis ([[1pjj]])<ref>PMID: 16243784</ref>, Bacillus Stereothermophilus ([[1r2y]])<ref>PMID:14525999</ref>, Thermos Thermophilus ([[1ee8]])<ref>PMID:10921868</ref> and Escherichia Coli([[1k82]])<ref>PMID:11912217</ref> and Nei from Escherichia Coli ([[1k3w]])<ref>PMID:11847126</ref>, as well as human Neil1 ([[1tdh]])<ref>PMID:19625256</ref>and mimivirus Nei ([[3a42]])<ref>PMID:17627905</ref>. The overall structure is similar, and some of the damages include 8-oxoguanine and fapyG ([[1xc8]])<ref>PMID:15249553</ref>.
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and <scene name='User:Ramiro_Barrantes/Workbench/Neil1zinclessfinger/3' target="ecoNei"> click here for the Neil1 zincless finger, an equivalent structure without the zinc nor the cysteines.</scene></p>
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<p>The Zinc finger (of the β/β-antiparallel CCCC type) serves to hold the absolutely conserved Arg264 residue <ref>PMID:11847126</ref>, which binds to the phosphate of the damaged base and is crucial for function (mutation of this site results in failed cleavage of the damaged base <ref>PMID:11847126</ref>). Site directed mutagenesis experiments have been performed on all four cysteines, leading to loss of activity <ref>PMID:8473347</ref><ref>PMID: 8253809 </ref>, emphasizing the importance of this LSC. In Neil1, there is no Zinc but there is an equivalent structure: a "zincless finger" <ref>PMID:15232006</ref>. Both the plants and mimivirus have a zincless finger as well <ref>PMID:19217358</ref><ref>PMID:17627905</ref>, although it is not clear if these are all homologous.</p>
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</td></tr>
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<tr valign="top"><td>
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=== LSC7: Recognition Complex ===
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This complex is key in recognizing a damaged guanine<ref>PMID:14525999</ref>
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</td>
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<td>
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</td>
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</tr>
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</table>
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== Zinc/zincless finger ==
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==Latent Structural Characters (LSCs)==
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[[Image:ZincFingerComparison.png|thumb|166px|right|Tyrosine that binds to DNA, the plant has a different structure alltogether]]
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{|
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| [[Image:LSCDiagram.png|thumb|500px|right|Diagram with the LSCs (yellow), their suggested role (arrows) and the amino acids or features they affect (green and blue)]] We define a latent structural character (LSC) as neighboring amino acids which have changed in rate or constraint for a given clade or set of clades. For example, the cysteines in the zinc finger are all conserved in the fpg1, fpg2, actinobacterial and eukaryotic clades, but have a higher rate in plants and neil1, as the latter have a zinc-less finger (see [http://proteopedia.org/wiki/index.php?title=User:Ramiro_Barrantes/Workbench/LSC6 here] for more information). We developed a novel method to find these groups of amino acids, discovering previously unknown groups of amino acids which are functionally important in some of these subfamilies.
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The table below has some of our main findings, there are two variants for each LSC in case that for one LSC there is a compensating cluster in the other subfamilies. If you click on one of them you will see the result in the structure, and you can go to the explanation and the sequence distribution below. <br> [http://xpdb.nist.gov/hivsdb/jmol/jmol_help.html Click here for Jmol tutorial].|
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|}
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== Evolution ==
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{| - style="font-size:18px;align=center"
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The FpgNei evolution has not been easy to resolve <ref>PMID:15232006</ref>, especially in the deeper branches. Assuming that functional clusters evolve more slowly than individual residues, we can use this as phylogenetic characters to 1) draw the most parsimonious evolution of the superfamily as dictated by these functional clusters 2) examine how these clusters have evolved and how this might have influenced the evolution of FpgNei.
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| <applet load='1R2Y' size='500' frame='true' align='left' name="fpg" scene='User:Ramiro_Barrantes/Workbench/Gstfpg/5'/>
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[[Image:Scenario1.png]]
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| <applet load='1K3W' size='500' frame='true' align='right' name="ecoNei" scene='User:Ramiro_Barrantes/Workbench/Econeiwater/1' />
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|}
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== Site-directed mutants ==
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{| class="wikitable" style="text-align:center"
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The following we intend to be comprehensive list of site-directed mutants from the literature. The description is just a very brief, and thus inaccurate summary. Please see the relevant reference for more information.
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{| valign="top"
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|
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{| class="wikitable" style="text-align:center"
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| Name || Organism/Structure || Effect || Reference
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|-
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| <scene name='User:Ramiro_Barrantes/Workbench/P2t/1' target="ecoNeiMutants">EcoNei P1T</scene> || ''E. coli'' Nei ([[1k3w]]) || Inactive but can still make Schiff Base. || <ref>PMID:11711552</ref>
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! Functional Cluster !! State 1 !! State 2 !! Fpg1 !! Fpg2 !! Plant !! Neil1 !! Neil2 !! Neil3 !! Proteo !! Actino1 !! Actino2 !! MimiVirus
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|-
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| <scene name='User:Ramiro_Barrantes/Workbench/Econei/6' target="ecoNeiMutants">EcoNei E2A,E2Q</scene> || ''E. coli'' Nei ([[1k3w]]) || inactive || <ref>PMID:16145054</ref><ref>PMID:11847126</ref>
+
| Support for perfectly conserved residue
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Lys160asp178/13' target="fpg">Lys160 and Asp178</scene>
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Econeiarginine171/10' target="ecoNei">Arg171</scene>
 +
| 1 || 1 || 1 || 0 || 0 || 0 || 0 || 0 || 0 || 0
|-
|-
-
| <scene name='User:Ramiro_Barrantes/Workbench/Glu3/1' target="ecoNeiMutants">EcoNei E3A</scene> || ''E. coli'' Nei ([[1k3w]]) || Decrease glycosylase, lyase ok. || <ref>PMID:11711552</ref>
+
| Stability of catalytic helix
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgglu8arg57leu4triad/8' target="fpg">Leu4,Glu8,Arg57</scene>
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Econeisupporttriadcounterpart/5' target="ecoNei">Different</scene>
 +
| 1 || 1 || 1 || - || - || - || - || - || - || -
|-
|-
-
| <scene name='User:Ramiro_Barrantes/Workbench/Glu3/1' target="ecoNeiMutants">EcoNei E3Q</scene> || ''E. coli'' Nei ([[1k3w]]) || Decrease glycosylase, lyase ok. || <ref>PMID:11711552</ref>
+
| Neil1-specific: Stability of Lys60
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgneil1covariate/5' target="fpg">E137,R58,G135,L134</scene>
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Neil1lys60support/3' target="ecoNei">Covariation with Asn172</scene>
 +
| 1 || 1 || 1|| 0 || 1 || 1 || 1 || 1 || 1 || 1
|-
|-
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeiwaterlys57/2' target="ecoNeiMutants">EcoFpg K57G,EcoNei K52A</scene> || ''E. coli'' Fpg ([[1k82]])|| reduced glygosylase, less efficient in Schiff-base complex. No cleavage. || <ref>PMID:9826758</ref><ref>PMID:11847126</ref>
+
| Intercalation loop
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Fpgintercalationloop/3' target="fpg">D110,F108,R113,R112,F114</scene>
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Econeiintercalationloop/4' target="ecoNei">Gln76,Met77,Tyr78</scene>
 +
| 1 || 1 || 1 || - || - || - || - || - || - || 1
|-
|-
-
| <scene name='User:Ramiro_Barrantes/Workbench/Bste77s/1' target="ecoNeiMutants">EcoFpg E77S</scene> || ''B. stereo'' Fpg ([[1r2y]])|| Switches preferences for syn and anti in 8oxoG || <ref>PMID:16953574</ref>
+
| PlantFungi-specific: R254 DNA binding
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgtyr243/4' target="fpg">Y242,G243,R244</scene>
 +
| different in plants
 +
| 1 || 1 || 0 || 1 || 1 || 1 || 2 || 1 || 1 || 1
|-
|-
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeiintercalationloop/2' target="ecoNeiMutants">EcoNei 77-79 QLY/AAA, delQLY</scene> || ''E. coli'' Nei ([[1k3w]])|| Decreased or no activity || <ref>PMID:17002303</ref>
+
| Zinc/zincless finger
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgzincfinger/6' target="fpg">Zinc finger</scene>
 +
| <scene name='User:Ramiro_Barrantes/Workbench/Neil1zinclessfinger/5' target="ecoNei">Neil1 zincless finger</scene>
 +
| 1 || 1 || - || - || 1 || 1 || 1 || 1 || 1 || -
|-
|-
-
| <scene name='User:Ramiro_Barrantes/Workbench/Ecofpgh89/1' target="ecoNeiMutants">EcoFpg H89A</scene> || ''E. coli'' Fpg ([[1k82]])|| reduced rate of excision || <ref>PMID:14607836</ref>
+
| Recognition complex
-
|-
+
| <scene name='User:Ramiro_Barrantes/Workbench/Gstfpgrecognitioncomplex/1' target="fpg">Loop from Gly218 to Gly233</scene>
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeil90/1' target="ecoNeiMutants">EcoNei L90S</scene> || ''E. coli'' Nei ([[1k3w]]) || Active but different kinetics. || <ref>PMID:11580290</ref>
+
| <scene name='User:Ramiro_Barrantes/Workbench/LSCs/Neil1helixalpha10beta9/1' target="ecoNei">Helix in Neil1</scene>
-
|-
+
| 1 || - || - || - || - || - || - || - || - || -
-
| <scene name='User:Ramiro_Barrantes/Workbench/Ecofpgr109a/1' target="ecoNeiMutants">EcoFpg R109A</scene> || ''E. coli'' Fpg ([[1k82]])|| Abolished binding || <ref>PMID:14607836</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Ecofpgf110af110w/1' target="ecoNeiMutants">EcoFpg F110A/F110W</scene> || ''E. coli'' Fpg ([[1k82]])|| Decreases processivity|| <ref>PMID:18672903</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeid129/1' target="ecoNeiMutants">EcoNei D129A</scene> || ''E. coli'' Nei ([[1k3w]])|| same || <ref>PMID:11711552</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Ecofpgk155/1' target="ecoNeiMutants">EcoFpg K155</scene> || ''E. coli'' Fpg ([[1k82]])|| reduced glygosylase, less efficient in Schiff-base complex. No cleavage. || <ref>PMID:9125531</ref><ref>PMID:11554299</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeid160n/1' target="ecoNeiMutants">EcoNei D160N</scene> || ''E. coli'' Nei ([[1k3w]])|| same || <ref>PMID:11711552</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeiarginine171/3' target="ecoNeiMutants">EcoNei R171</scene> || ''E. coli'' Nei ([[1k3w]])|| reduced activity, loss of opposite base discrimination || <ref>PMID:17002303</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeid174/1' target="ecoNeiMutants">EcoNei E174Q</scene> || ''E. coli'' Nei ([[1k3w]])|| ok lyase, reduced glycosylase || <ref>PMID:11711552</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeir212/1' target="ecoNeiMutants">EcoNei R212A</scene> || ''E. coli'' Nei ([[1k3w]]) || Decreased activity on 5S,6R Tg, slightly less active on DHU|| <ref>PMID:11847126</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Bstfpgr223ecofpgk217/1' target="ecoNeiMutants">EcoFpg K217A</scene> || ''B. stereo'' Fpg ([[1r2y]])|| Selectively reduced excision ability|| <ref>PMID:14607836</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeir252/1' target="ecoNeiMutants">EcoNei R252A</scene> || ''E. coli'' Nei ([[1k3w]]) || inactive, although can cleave AP sites || <ref>PMID:16145054</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Neil1glu28/1' target="ecoNeiMutants">humanNeil1 Glu28del</scene> || ''H. Sapiens Neil1'' ([[1tdh]]) || Low activity || <ref>PMID:15319300</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Ecofpgzincfinger/1' target="ecoNeiMutants">ecoFpg C244(S/H,A)</scene> || ''E. coli'' Fpg ([[1k82]]) || No binding nor cleavage || <ref>PMID:8253809</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Ecofpgzincfingerwithcys247244/1' target="ecoNeiMutants">ecoFpg C244S/C247S)</scene> || ''E. coli'' Fpg ([[1k82]]) || No binding nor cleavage. No zinc, no altered secondary structure || <ref>PMID:8253809</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Econeiq261/1' target="ecoNeiMutants">ecoNei Q261</scene> || ''E. coli'' Nei ([[1k3w]]) || Loss of activity || <ref>PMID:17002303</ref>
+
-
|-
+
-
| <scene name='User:Ramiro_Barrantes/Workbench/Ecofpgzincfingerwithallcystein/1' target="ecoNeiMutants">ecoFpg any of: C244G,C247G,C264G,C267G</scene> || ''E. coli'' Fpg ([[1k82]]) || No lyase nor glycosylase || <ref>PMID:8473347</ref>
+
-
|}
+
-
| <applet load='1K3W' size='500' frame='true' align='left' caption='See structure column for structure reference' name="ecoNeiMutants" scene='User:Ramiro_Barrantes/Workbench/Econeiwater/1' />
+
|}
|}
 +
 +
== Evolution ==
 +
The FpgNei evolution has not been easy to resolve <ref>PMID:15232006</ref>, especially in the deeper branches. Assuming that functional clusters evolve more slowly than individual residues, we can use this as phylogenetic characters to 1) draw the most parsimonious evolution of the superfamily as dictated by these functional clusters 2) examine how these clusters have evolved and how this might have influenced the evolution of FpgNei.
 +
[[Image:Scenario1.png|thumb|500px|right|Gene evolution of the Fpg/Nei protein family. The root is placed in the Fpg branch given its broad distribution among bacteria.)]]
==References==
==References==
<references />
<references />

Current revision


The FpgNei Protein Family 

  1. Background on DNA Repair 

  2. Background on Fpg/Nei

     2.1 Overall Function and Structure

  3. Latent Structural Characters Summary

  5. References

Background on DNA Repair

The genome of any living organism is continuously affected by exogenous and endogenous agents, such as ultraviolet light, ionizing radiation, different chemicals and the cell's own metabolites (such as reactive oxygen). Therefore, different systems have evolved to repair these damages, with some of these systems shared throughout all lifeforms. Therefore, the proper functioning of DNA repair is critical for survival. There are six pathways of DNA repair (reviewed in Friedberg et al), which include base-excision repair. The latter's distinguishing feature is that it removes lesions as single bases, as opposed to dNMPs or short oligonucleotides like other systems. [1]

Base excision repair's signature enzyme are the DNA glycosylases. These enzymes work by recognizing a damaged base, and then hydrolizing the N-glycosidic bond of the damaged deoxynucleoside and thus removing a single damaged base from DNA. The subsequent steps of the pathway (strand incision, gap-filling and ligation) are done by other enzymes. [2][3]

Background on Fpg Nei

Overall Function and Structure

(For FPG, the structure used was 1r2y and for Nei 1k3w) Members of this family have . When enzyme binds to DNA, the damaged base

, with . This superfamily is also characterized by containing a ; as well as a . Both the H2TH motif and the Zinc finger, as well as other residues . [4]. Catalysis is believed to be mediated by . For information on the mechanism please consult [5][6][7][8][9].

Similarly In EcoNei (structure 1k3w, , and (Thymine Glycol in the case of Nei). [10]. Some of these amino acids are stabilized by [a (although a zincless finger motif is present in some of these subfamilies [11]). Analogously to Fpg, ), Note that the last two elements discussed, the zinc vs. zincless finger, and the two kinds of intercalation loops, are examples of coevolving functional clusters, groups of amino acids that perform a function, and that might be unnecessary or compensated for within the other subfamilies. We developed a novel method for identifying these clusters and have applied it to bring insight into the structure, function and evolution FpgNei family.

See structure column for structure reference

Drag the structure with the mouse to rotate
===Phylogeny===
Cartoon phylogenetic tree of the FpgNei protein family. Note that this phylogeny can be appreciated in two levels: by the distribution and number of FpgNei subfamilies in different organisms; and by the kinds of damages that can be repaired (see table on the right)
Cartoon phylogenetic tree of the FpgNei protein family. Note that this phylogeny can be appreciated in two levels: by the distribution and number of FpgNei subfamilies in different organisms; and by the kinds of damages that can be repaired (see table on the right)
===Table of preferred substrates===
Clade Function References
Fpg 8oxoG, Fapy-A, Fapy-G,Me-Fapy-G,Sp,Gh [12][13]
EcoNei Oxidized pyrimidines [14]
Actinomycetes Nei1 DHU [15]
Actinomycetes Nei2  ?
Fpg2  ?
Plant&Fungi Sp,Gh [16]
Neil1 Sp,Gh,on double&single strand DNA, Both stereoisomers of Tg [17][18]
Neil2 Sp,Gh,on double&single stranded DNA [19]
Neil3 not clear [20]

Mechanisms

Several authors have suggested mechanisms for these enzymes, please see references for more information [21][22][23][24].

Solved Structures

Homologous structures have been solved, including Fpg protein from Lactococcus Lactis (1pjj)[25], Bacillus Stereothermophilus (1r2y)[26], Thermos Thermophilus (1ee8)[27] and Escherichia Coli(1k82)[28] and Nei from Escherichia Coli (1k3w)[29], as well as human Neil1 (1tdh)[30]and mimivirus Nei (3a42)[31]. The overall structure is similar, and some of the damages include 8-oxoguanine and fapyG (1xc8)[32].

Latent Structural Characters (LSCs)

Diagram with the LSCs (yellow), their suggested role (arrows) and the amino acids or features they affect (green and blue)
Diagram with the LSCs (yellow), their suggested role (arrows) and the amino acids or features they affect (green and blue)
We define a latent structural character (LSC) as neighboring amino acids which have changed in rate or constraint for a given clade or set of clades. For example, the cysteines in the zinc finger are all conserved in the fpg1, fpg2, actinobacterial and eukaryotic clades, but have a higher rate in plants and neil1, as the latter have a zinc-less finger (see here for more information). We developed a novel method to find these groups of amino acids, discovering previously unknown groups of amino acids which are functionally important in some of these subfamilies.

The table below has some of our main findings, there are two variants for each LSC in case that for one LSC there is a compensating cluster in the other subfamilies. If you click on one of them you will see the result in the structure, and you can go to the explanation and the sequence distribution below.
Click here for Jmol tutorial.|

PDB ID 1R2Y

Drag the structure with the mouse to rotate

PDB ID 1K3W

Drag the structure with the mouse to rotate
Functional Cluster State 1 State 2 Fpg1 Fpg2 Plant Neil1 Neil2 Neil3 Proteo Actino1 Actino2 MimiVirus
Support for perfectly conserved residue 1 1 1 0 0 0 0 0 0 0
Stability of catalytic helix 1 1 1 - - - - - - -
Neil1-specific: Stability of Lys60 1 1 1 0 1 1 1 1 1 1
Intercalation loop 1 1 1 - - - - - - 1
PlantFungi-specific: R254 DNA binding different in plants 1 1 0 1 1 1 2 1 1 1
Zinc/zincless finger 1 1 - - 1 1 1 1 1 -
Recognition complex 1 - - - - - - - - -

Evolution

The FpgNei evolution has not been easy to resolve [33], especially in the deeper branches. Assuming that functional clusters evolve more slowly than individual residues, we can use this as phylogenetic characters to 1) draw the most parsimonious evolution of the superfamily as dictated by these functional clusters 2) examine how these clusters have evolved and how this might have influenced the evolution of FpgNei.

Gene evolution of the Fpg/Nei protein family. The root is placed in the Fpg branch given its broad distribution among bacteria.)
Gene evolution of the Fpg/Nei protein family. The root is placed in the Fpg branch given its broad distribution among bacteria.)

References

  1. ↑ Zharkov DO. Base excision DNA repair. Cell Mol Life Sci. 2008 May;65(10):1544-65. PMID:18259689 doi:10.1007/s00018-008-7543-2
  2. ↑ Zharkov DO. Base excision DNA repair. Cell Mol Life Sci. 2008 May;65(10):1544-65. PMID:18259689 doi:10.1007/s00018-008-7543-2
  3. ↑ Robertson AB, Klungland A, Rognes T, Leiros I. DNA repair in mammalian cells: Base excision repair: the long and short of it. Cell Mol Life Sci. 2009 Mar;66(6):981-93. PMID:19153658 doi:10.1007/s00018-009-8736-z
  4. ↑ Gilboa R, Zharkov DO, Golan G, Fernandes AS, Gerchman SE, Matz E, Kycia JH, Grollman AP, Shoham G. Structure of formamidopyrimidine-DNA glycosylase covalently complexed to DNA. J Biol Chem. 2002 May 31;277(22):19811-6. Epub 2002 Mar 23. PMID:11912217 doi:http://dx.doi.org/10.1074/jbc.M202058200
  5. ↑ Pereira de Jesus K, Serre L, Zelwer C, Castaing B. Structural insights into abasic site for Fpg specific binding and catalysis: comparative high-resolution crystallographic studies of Fpg bound to various models of abasic site analogues-containing DNA. Nucleic Acids Res. 2005 Oct 20;33(18):5936-44. Print 2005. PMID:16243784 doi:http://dx.doi.org/33/18/5936
  6. ↑ Zharkov DO, Golan G, Gilboa R, Fernandes AS, Gerchman SE, Kycia JH, Rieger RA, Grollman AP, Shoham G. Structural analysis of an Escherichia coli endonuclease VIII covalent reaction intermediate. EMBO J. 2002 Feb 15;21(4):789-800. PMID:11847126 doi:10.1093/emboj/21.4.789
  7. ↑ Coste F, Ober M, Carell T, Boiteux S, Zelwer C, Castaing B. Structural basis for the recognition of the FapydG lesion (2,6-diamino-4-hydroxy-5-formamidopyrimidine) by formamidopyrimidine-DNA glycosylase. J Biol Chem. 2004 Oct 15;279(42):44074-83. Epub 2004 Jul 10. PMID:15249553 doi:10.1074/jbc.M405928200
  8. ↑ Gilboa R, Zharkov DO, Golan G, Fernandes AS, Gerchman SE, Matz E, Kycia JH, Grollman AP, Shoham G. Structure of formamidopyrimidine-DNA glycosylase covalently complexed to DNA. J Biol Chem. 2002 May 31;277(22):19811-6. Epub 2002 Mar 23. PMID:11912217 doi:http://dx.doi.org/10.1074/jbc.M202058200
  9. ↑ Sugahara M, Mikawa T, Kumasaka T, Yamamoto M, Kato R, Fukuyama K, Inoue Y, Kuramitsu S. Crystal structure of a repair enzyme of oxidatively damaged DNA, MutM (Fpg), from an extreme thermophile, Thermus thermophilus HB8. EMBO J. 2000 Aug 1;19(15):3857-69. PMID:10921868 doi:http://dx.doi.org/10.1093/emboj/19.15.3857
  10. ↑ Zharkov DO, Golan G, Gilboa R, Fernandes AS, Gerchman SE, Kycia JH, Rieger RA, Grollman AP, Shoham G. Structural analysis of an Escherichia coli endonuclease VIII covalent reaction intermediate. EMBO J. 2002 Feb 15;21(4):789-800. PMID:11847126 doi:10.1093/emboj/21.4.789
  11. ↑ Doublie S, Bandaru V, Bond JP, Wallace SS. The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity. Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10284-9. Epub 2004 Jul 1. PMID:15232006 doi:10.1073/pnas.0402051101
  12. ↑ Leipold MD, Muller JG, Burrows CJ, David SS. Removal of hydantoin products of 8-oxoguanine oxidation by the Escherichia coli DNA repair enzyme, FPG. Biochemistry. 2000 Dec 5;39(48):14984-92. PMID:11101315
  13. ↑ David SS, Williams SD. Chemistry of Glycosylases and Endonucleases Involved in Base-Excision Repair. Chem Rev. 1998 May 7;98(3):1221-1262. PMID:11848931
  14. ↑ Jiang D, Hatahet Z, Melamede RJ, Kow YW, Wallace SS. Characterization of Escherichia coli endonuclease VIII. J Biol Chem. 1997 Dec 19;272(51):32230-9. PMID:9405426
  15. ↑ Sidorenko VS, Rot MA, Filipenko ML, Nevinsky GA, Zharkov DO. Novel DNA glycosylases from Mycobacterium tuberculosis. Biochemistry (Mosc). 2008 Apr;73(4):442-50. PMID:18457574
  16. ↑ Kathe SD, Barrantes-Reynolds R, Jaruga P, Newton MR, Burrows CJ, Bandaru V, Dizdaroglu M, Bond JP, Wallace SS. Plant and fungal Fpg homologs are formamidopyrimidine DNA glycosylases but not 8-oxoguanine DNA glycosylases. DNA Repair (Amst). 2009 May 1;8(5):643-53. Epub 2009 Feb 12. PMID:19217358 doi:10.1016/j.dnarep.2008.12.013
  17. ↑ Hailer MK, Slade PG, Martin BD, Rosenquist TA, Sugden KD. Recognition of the oxidized lesions spiroiminodihydantoin and guanidinohydantoin in DNA by the mammalian base excision repair glycosylases NEIL1 and NEIL2. DNA Repair (Amst). 2005 Jan 2;4(1):41-50. PMID:15533836 doi:10.1016/j.dnarep.2004.07.006
  18. ↑ Rosenquist TA, Zaika E, Fernandes AS, Zharkov DO, Miller H, Grollman AP. The novel DNA glycosylase, NEIL1, protects mammalian cells from radiation-mediated cell death. DNA Repair (Amst). 2003 May 13;2(5):581-91. PMID:12713815
  19. ↑ Hailer MK, Slade PG, Martin BD, Rosenquist TA, Sugden KD. Recognition of the oxidized lesions spiroiminodihydantoin and guanidinohydantoin in DNA by the mammalian base excision repair glycosylases NEIL1 and NEIL2. DNA Repair (Amst). 2005 Jan 2;4(1):41-50. PMID:15533836 doi:10.1016/j.dnarep.2004.07.006
  20. ↑ Takao M, Oohata Y, Kitadokoro K, Kobayashi K, Iwai S, Yasui A, Yonei S, Zhang QM. Human Nei-like protein NEIL3 has AP lyase activity specific for single-stranded DNA and confers oxidative stress resistance in Escherichia coli mutant. Genes Cells. 2009 Feb;14(2):261-70. Epub 2008 Jan 15. PMID:19170771 doi:10.1111/j.1365-2443.2008.01271.x
  21. ↑ Zharkov DO, Golan G, Gilboa R, Fernandes AS, Gerchman SE, Kycia JH, Rieger RA, Grollman AP, Shoham G. Structural analysis of an Escherichia coli endonuclease VIII covalent reaction intermediate. EMBO J. 2002 Feb 15;21(4):789-800. PMID:11847126 doi:10.1093/emboj/21.4.789
  22. ↑ Sugahara M, Mikawa T, Kumasaka T, Yamamoto M, Kato R, Fukuyama K, Inoue Y, Kuramitsu S. Crystal structure of a repair enzyme of oxidatively damaged DNA, MutM (Fpg), from an extreme thermophile, Thermus thermophilus HB8. EMBO J. 2000 Aug 1;19(15):3857-69. PMID:10921868 doi:http://dx.doi.org/10.1093/emboj/19.15.3857
  23. ↑ Pereira de Jesus K, Serre L, Zelwer C, Castaing B. Structural insights into abasic site for Fpg specific binding and catalysis: comparative high-resolution crystallographic studies of Fpg bound to various models of abasic site analogues-containing DNA. Nucleic Acids Res. 2005 Oct 20;33(18):5936-44. Print 2005. PMID:16243784 doi:http://dx.doi.org/33/18/5936
  24. ↑ Gilboa R, Zharkov DO, Golan G, Fernandes AS, Gerchman SE, Matz E, Kycia JH, Grollman AP, Shoham G. Structure of formamidopyrimidine-DNA glycosylase covalently complexed to DNA. J Biol Chem. 2002 May 31;277(22):19811-6. Epub 2002 Mar 23. PMID:11912217 doi:http://dx.doi.org/10.1074/jbc.M202058200
  25. ↑ Pereira de Jesus K, Serre L, Zelwer C, Castaing B. Structural insights into abasic site for Fpg specific binding and catalysis: comparative high-resolution crystallographic studies of Fpg bound to various models of abasic site analogues-containing DNA. Nucleic Acids Res. 2005 Oct 20;33(18):5936-44. Print 2005. PMID:16243784 doi:http://dx.doi.org/33/18/5936
  26. ↑ Fromme JC, Verdine GL. DNA lesion recognition by the bacterial repair enzyme MutM. J Biol Chem. 2003 Dec 19;278(51):51543-8. Epub 2003 Oct 1. PMID:14525999 doi:10.1074/jbc.M307768200
  27. ↑ Sugahara M, Mikawa T, Kumasaka T, Yamamoto M, Kato R, Fukuyama K, Inoue Y, Kuramitsu S. Crystal structure of a repair enzyme of oxidatively damaged DNA, MutM (Fpg), from an extreme thermophile, Thermus thermophilus HB8. EMBO J. 2000 Aug 1;19(15):3857-69. PMID:10921868 doi:http://dx.doi.org/10.1093/emboj/19.15.3857
  28. ↑ Gilboa R, Zharkov DO, Golan G, Fernandes AS, Gerchman SE, Matz E, Kycia JH, Grollman AP, Shoham G. Structure of formamidopyrimidine-DNA glycosylase covalently complexed to DNA. J Biol Chem. 2002 May 31;277(22):19811-6. Epub 2002 Mar 23. PMID:11912217 doi:http://dx.doi.org/10.1074/jbc.M202058200
  29. ↑ Zharkov DO, Golan G, Gilboa R, Fernandes AS, Gerchman SE, Kycia JH, Rieger RA, Grollman AP, Shoham G. Structural analysis of an Escherichia coli endonuclease VIII covalent reaction intermediate. EMBO J. 2002 Feb 15;21(4):789-800. PMID:11847126 doi:10.1093/emboj/21.4.789
  30. ↑ Imamura K, Wallace SS, Doublie S. Structural characterization of a viral NEIL1 ortholog unliganded and bound to abasic site-containing DNA. J Biol Chem. 2009 Sep 18;284(38):26174-83. Epub 2009 Jul 22. PMID:19625256 doi:10.1074/jbc.M109.021907
  31. ↑ Bandaru V, Zhao X, Newton MR, Burrows CJ, Wallace SS. Human endonuclease VIII-like (NEIL) proteins in the giant DNA Mimivirus. DNA Repair (Amst). 2007 Nov;6(11):1629-41. Epub 2007 Jul 12. PMID:17627905 doi:10.1016/j.dnarep.2007.05.011
  32. ↑ Coste F, Ober M, Carell T, Boiteux S, Zelwer C, Castaing B. Structural basis for the recognition of the FapydG lesion (2,6-diamino-4-hydroxy-5-formamidopyrimidine) by formamidopyrimidine-DNA glycosylase. J Biol Chem. 2004 Oct 15;279(42):44074-83. Epub 2004 Jul 10. PMID:15249553 doi:10.1074/jbc.M405928200
  33. ↑ Doublie S, Bandaru V, Bond JP, Wallace SS. The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity. Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10284-9. Epub 2004 Jul 1. PMID:15232006 doi:10.1073/pnas.0402051101

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