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User:Marcos Ngo/Sandbox 1
From Proteopedia
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<StructureSection load='7rds' size='340' side='right'caption='[[7rds]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='7rds' size='340' side='right'caption='[[7rds]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/NTH_HUMAN NTH_HUMAN] Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage (PubMed:9927729). The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines. Has also 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts preferentially on DNA damage opposite guanine residues in DNA. Is able to process lesions in nucleosomes without requiring or inducing nucleosome disruption.[HAMAP-Rule:MF_03183]<ref>PMID:10882850</ref> <ref>PMID:11328882</ref> <ref>PMID:11380260</ref> <ref>PMID:11695910</ref> <ref>PMID:12140329</ref> <ref>PMID:12144783</ref> <ref>PMID:12519758</ref> <ref>PMID:14734554</ref> <ref>PMID:15533839</ref> <ref>PMID:17923696</ref> <ref>PMID:20005182</ref> <ref>PMID:20110254</ref> <ref>PMID:21930793</ref> <ref>PMID:8990169</ref> <ref>PMID:9045706</ref> <ref>PMID:9705289</ref> <ref>PMID:9890904</ref> <ref>PMID:9927729</ref> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7rds]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. hNTHL1 has two <scene name='10/1077482/Domains/3'>Domains</scene> connected with two <scene name='10/1077482/Linkers/2'>linkers</scene>. Domain 1 has the <scene name='10/1077482/Fes_proper/1'>FeS </scene> cluster, the <scene name='10/1077482/N_and_c_terminus/1'>N-terminus, the C-terminus </scene> and one catalytic residue <scene name='10/1077482/Asp/1'>(Asp)</scene>. The second domain has the other catalytic residue (<scene name='10/1077482/Lysine/4'>Lys</scene>),a six-helical barrel domain, and a HhH motif. It is captured in an open conformation with a conformational change being required for the catalytic residues to assembled. <ref>PMID:34871433</ref> | <table><tr><td colspan='2'>[[7rds]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. hNTHL1 has two <scene name='10/1077482/Domains/3'>Domains</scene> connected with two <scene name='10/1077482/Linkers/2'>linkers</scene>. Domain 1 has the <scene name='10/1077482/Fes_proper/1'>FeS </scene> cluster, the <scene name='10/1077482/N_and_c_terminus/1'>N-terminus, the C-terminus </scene> and one catalytic residue <scene name='10/1077482/Asp/1'>(Asp)</scene>. The second domain has the other catalytic residue (<scene name='10/1077482/Lysine/4'>Lys</scene>),a six-helical barrel domain, and a HhH motif. It is captured in an open conformation with a conformational change being required for the catalytic residues to assembled. <ref>PMID:34871433</ref> | ||
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Role of <scene name='10/1077482/Fes_proper/1'>FeS </scene> Cluster | Role of <scene name='10/1077482/Fes_proper/1'>FeS </scene> Cluster | ||
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Flexible linker... | Flexible linker... | ||
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<br> | <br> | ||
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7rds FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rds OCA], [https://pdbe.org/7rds PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rds RCSB], [https://www.ebi.ac.uk/pdbsum/7rds PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rds ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7rds FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rds OCA], [https://pdbe.org/7rds PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rds RCSB], [https://www.ebi.ac.uk/pdbsum/7rds PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rds ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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== Disease == | == Disease == | ||
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<scene name='10/1077482/Fes/1'>FeS</scene> | <scene name='10/1077482/Fes/1'>FeS</scene> | ||
| - | == Function == | ||
| - | [https://www.uniprot.org/uniprot/NTH_HUMAN NTH_HUMAN] Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage (PubMed:9927729). The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines. Has also 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts preferentially on DNA damage opposite guanine residues in DNA. Is able to process lesions in nucleosomes without requiring or inducing nucleosome disruption.[HAMAP-Rule:MF_03183]<ref>PMID:10882850</ref> <ref>PMID:11328882</ref> <ref>PMID:11380260</ref> <ref>PMID:11695910</ref> <ref>PMID:12140329</ref> <ref>PMID:12144783</ref> <ref>PMID:12519758</ref> <ref>PMID:14734554</ref> <ref>PMID:15533839</ref> <ref>PMID:17923696</ref> <ref>PMID:20005182</ref> <ref>PMID:20110254</ref> <ref>PMID:21930793</ref> <ref>PMID:8990169</ref> <ref>PMID:9045706</ref> <ref>PMID:9705289</ref> <ref>PMID:9890904</ref> <ref>PMID:9927729</ref> | ||
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== Relevance == | == Relevance == | ||
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<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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| - | == Publication Abstract from PubMed == | ||
| - | Base excision repair (BER) is the main pathway protecting cells from the continuous damage to DNA inflicted by reactive oxygen species. BER is initiated by DNA glycosylases, each of which repairs a particular class of base damage. NTHL1, a bifunctional DNA glycosylase, possesses both glycolytic and beta-lytic activities with a preference for oxidized pyrimidine substrates. Defects in human NTHL1 drive a class of polyposis colorectal cancer. We report the first X-ray crystal structure of hNTHL1, revealing an open conformation not previously observed in the bacterial orthologs. In this conformation, the six-helical barrel domain comprising the helix-hairpin-helix (HhH) DNA binding motif is tipped away from the iron sulphur cluster-containing domain, requiring a conformational change to assemble a catalytic site upon DNA binding. We found that the flexibility of hNTHL1 and its ability to adopt an open configuration can be attributed to an interdomain linker. Swapping the human linker sequence for that of Escherichia coli yielded a protein chimera that crystallized in a closed conformation and had a reduced activity on lesion-containing DNA. This large scale interdomain rearrangement during catalysis is unprecedented for a HhH superfamily DNA glycosylase and provides important insight into the molecular mechanism of hNTHL1. | ||
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| - | Caught in motion: human NTHL1 undergoes interdomain rearrangement necessary for catalysis.,Carroll BL, Zahn KE, Hanley JP, Wallace SS, Dragon JA, Doublie S Nucleic Acids Res. 2021 Dec 16;49(22):13165-13178. doi: 10.1093/nar/gkab1162. PMID:34871433<ref>PMID:34871433</ref> | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Revision as of 18:35, 22 April 2025
==Structure of human NTHL1==
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