4ebc

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[[Image:4ebc.png|left|200px]]
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==Conformationally Restrained North-methanocarba-2'-deoxyadenosine Corrects the Error-Prone Nature of Human DNA Polymerase Iota==
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<StructureSection load='4ebc' size='340' side='right' caption='[[4ebc]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4ebc]] 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=4EBC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EBC FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0OH:NORTH-METHANOCARBA-2-DEOXYADENOSINE+TRIPHOSPHATE'>0OH</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<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>
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<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]], [[4ebd|4ebd]], [[4ebe|4ebe]]</td></tr>
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<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>
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<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>
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<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=4ebc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ebc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ebc RCSB], [http://www.ebi.ac.uk/pdbsum/4ebc PDBsum]</span></td></tr>
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</table>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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{{STRUCTURE_4ebc| PDB=4ebc | SCENE= }}
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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>
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===Conformationally Restrained North-methanocarba-2'-deoxyadenosine Corrects the Error-Prone Nature of Human DNA Polymerase Iota===
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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{{ABSTRACT_PUBMED_22632140}}
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==See Also==
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*[[DNA polymerase|DNA polymerase]]
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==About this Structure==
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== References ==
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[[4ebc]] 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=4EBC OCA].
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<references/>
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__TOC__
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==Reference==
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</StructureSection>
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<ref group="xtra">PMID:022632140</ref><references group="xtra"/>
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[[Category: DNA-directed DNA polymerase]]
[[Category: DNA-directed DNA polymerase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Banerjee, S.]]
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[[Category: Banerjee, S]]
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[[Category: Eoff, R L.]]
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[[Category: Eoff, R L]]
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[[Category: Ketkar, A.]]
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[[Category: Ketkar, A]]
[[Category: Polymerase]]
[[Category: Polymerase]]
[[Category: Transferase-dna complex]]
[[Category: Transferase-dna complex]]

Revision as of 03:52, 25 December 2014

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

4ebc, resolution 2.90Å

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