4ebd

From Proteopedia

(Difference between revisions)

Revision as of 13:41, 24 December 2014

Conformationally Restrained North-methanocarba-2'-deoxyadenosine Corrects the Error-Prone Nature of Human DNA Polymerase Iota

Structural highlights

4ebd is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
NonStd Res:
Related:	1t3n, 2alz, 3gv5, 3gv7, 3gv8, 3h40, 4ebc, 4ebe
Gene:	POLI, RAD30B (Homo sapiens)
Activity:	DNA-directed DNA polymerase, with EC number 2.7.7.7
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[POLI_HUMAN] Error-prone DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Favors Hoogsteen base-pairing in the active site. Inserts the correct base with high-fidelity opposite an adenosine template. Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine. May play a role in hypermutation of immunogobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

Y-family DNA polymerases participate in replication stress and DNA damage tolerance mechanisms. The properties that allow these enzymes to copy past bulky adducts or distorted template DNA can result in a greater propensity for them to make mistakes. Of the four human Y-family members, human DNA polymerase iota (hpol iota) is the most error-prone. In the current study, we elucidate the molecular basis for improving the fidelity of hpol iota through use of the fixed-conformation nucleotide North-methanocarba-2'-deoxyadenosine triphosphate (N-MC-dATP). Three crystal structures were solved of hpol iota in complex with DNA containing a template 2'-deoxythymidine (dT) paired with an incoming dNTP or modified nucleotide triphosphate. The ternary complex of hpol iota inserting N-MC-dATP opposite dT reveals that the adenine ring is stabilized in the anti orientation about the pseudo-glycosyl torsion angle (chi), which mimics precisely the mutagenic arrangement of dGTP:dT normally preferred by hpol iota. The stabilized anti conformation occurs without notable contacts from the protein but likely results from constraints imposed by the bicyclo[3.1.0]hexane scaffold of the modified nucleotide. Unmodified dATP and South-MC-dATP each adopt syn glycosyl orientations to form Hoogsteen base pairs with dT. The Hoogsteen orientation exhibits weaker base stacking interactions and is less catalytically favorable than anti N-MC-dATP. Thus, N-MC-dATP corrects the error-prone nature of hpol iota by preventing the Hoog-steen base-pairing mode normally observed for hpol iota-catalyzed insertion of dATP opposite dT. These results provide a previously unrecognized means of altering the efficiency and the fidelity of a human translesion DNA polymerase.

A nucleotide analogue induced gain of function corrects the error-prone nature of human DNA polymerase iota.,Ketkar A, Zafar MK, Banerjee S, Marquez VE, Egli M, Eoff RL J Am Chem Soc. 2012 May 26. PMID:22632140^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tissier A, Frank EG, McDonald JP, Iwai S, Hanaoka F, Woodgate R. Misinsertion and bypass of thymine-thymine dimers by human DNA polymerase iota. EMBO J. 2000 Oct 2;19(19):5259-66. PMID:11013228 doi:http://dx.doi.org/10.1093/emboj/19.19.5259
↑ Bebenek K, Tissier A, Frank EG, McDonald JP, Prasad R, Wilson SH, Woodgate R, Kunkel TA. 5'-Deoxyribose phosphate lyase activity of human DNA polymerase iota in vitro. Science. 2001 Mar 16;291(5511):2156-9. PMID:11251121 doi:http://dx.doi.org/10.1126/science.1058386
↑ Frank EG, Tissier A, McDonald JP, Rapic-Otrin V, Zeng X, Gearhart PJ, Woodgate R. Altered nucleotide misinsertion fidelity associated with poliota-dependent replication at the end of a DNA template. EMBO J. 2001 Jun 1;20(11):2914-22. PMID:11387224 doi:http://dx.doi.org/10.1093/emboj/20.11.2914
↑ Faili A, Aoufouchi S, Flatter E, Gueranger Q, Reynaud CA, Weill JC. Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota. Nature. 2002 Oct 31;419(6910):944-7. PMID:12410315 doi:http://dx.doi.org/10.1038/nature01117
↑ Haracska L, Prakash L, Prakash S. A mechanism for the exclusion of low-fidelity human Y-family DNA polymerases from base excision repair. Genes Dev. 2003 Nov 15;17(22):2777-85. PMID:14630940 doi:10.1101/gad.1146103
↑ Washington MT, Minko IG, Johnson RE, Wolfle WT, Harris TM, Lloyd RS, Prakash S, Prakash L. Efficient and error-free replication past a minor-groove DNA adduct by the sequential action of human DNA polymerases iota and kappa. Mol Cell Biol. 2004 Jul;24(13):5687-93. PMID:15199127 doi:http://dx.doi.org/10.1128/MCB.24.13.5687-5693.2004
↑ Nair DT, Johnson RE, Prakash S, Prakash L, Aggarwal AK. Replication by human DNA polymerase-iota occurs by Hoogsteen base-pairing. Nature. 2004 Jul 15;430(6997):377-80. PMID:15254543 doi:10.1038/nature02692
↑ Ketkar A, Zafar MK, Banerjee S, Marquez VE, Egli M, Eoff RL. A nucleotide analogue induced gain of function corrects the error-prone nature of human DNA polymerase iota. J Am Chem Soc. 2012 May 26. PMID:22632140 doi:10.1021/ja304176q

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4ebd"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4ebd]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EBD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EBD FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0OJ:SOUTH-METHANOCARBA-2-DEOXYADENOSINE+TRIPHOSPHATE'>0OJ</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0OJ:SOUTH-METHANOCARBA-2-DEOXYADENOSINE+TRIPHOSPHATE'>0OJ</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</scene></td></tr>
+<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1t3n|1t3n]], [[2alz|2alz]], [[3gv5|3gv5]], [[3gv7|3gv7]], [[3gv8|3gv8]], [[3h40|3h40]], [[4ebc|4ebc]], [[4ebe|4ebe]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1t3n|1t3n]], [[2alz|2alz]], [[3gv5|3gv5]], [[3gv7|3gv7]], [[3gv8|3gv8]], [[3h40|3h40]], [[4ebc|4ebc]], [[4ebe|4ebe]]</td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POLI, RAD30B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POLI, RAD30B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] </span></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] </span></td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ebd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ebd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ebd RCSB], [http://www.ebi.ac.uk/pdbsum/4ebd PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ebd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ebd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ebd RCSB], [http://www.ebi.ac.uk/pdbsum/4ebd PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/POLI_HUMAN POLI_HUMAN]] Error-prone DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Favors Hoogsteen base-pairing in the active site. Inserts the correct base with high-fidelity opposite an adenosine template. Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine. May play a role in hypermutation of immunogobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity.<ref>PMID:11013228</ref> <ref>PMID:11251121</ref> <ref>PMID:11387224</ref> <ref>PMID:12410315</ref> <ref>PMID:14630940</ref> <ref>PMID:15199127</ref> <ref>PMID:15254543</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 16: / Line 18: @@
 A nucleotide analogue induced gain of function corrects the error-prone nature of human DNA polymerase iota.,Ketkar A, Zafar MK, Banerjee S, Marquez VE, Egli M, Eoff RL J Am Chem Soc. 2012 May 26. PMID:22632140<ref>PMID:22632140</ref>
-From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
@@ Line 27: / Line 29: @@
 [[Category: DNA-directed DNA polymerase]]
 [[Category: Homo sapiens]]
-[[Category: Banerjee, S.]]
+[[Category: Banerjee, S]]
-[[Category: Eoff, R L.]]
+[[Category: Eoff, R L]]
-[[Category: Ketkar, A.]]
+[[Category: Ketkar, A]]
 [[Category: Polymerase]]
 [[Category: Transferase-dna complex]]

4ebd

From Proteopedia

Revision as of 13:41, 24 December 2014

Conformationally Restrained North-methanocarba-2'-deoxyadenosine Corrects the Error-Prone Nature of Human DNA Polymerase Iota

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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