4q5v

From Proteopedia

(Difference between revisions)

Revision as of 09:10, 24 April 2019

Crystal structure of the catalytic core of human DNA polymerase alpha in ternary complex with an RNA-primed DNA template and aphidicolin

Structural highlights

4q5v is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	POLA1, POLA (HUMAN)
Activity:	DNA-directed DNA polymerase, with EC number 2.7.7.7
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[DPOLA_HUMAN] Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes.^[1]

Publication Abstract from PubMed

Natural tetracyclic diterpenoid aphidicolin is a potent and specific inhibitor of B-family DNA polymerases, haltering replication and possessing a strong antimitotic activity in human cancer cell lines. Clinical trials revealed limitations of aphidicolin as an antitumor drug because of its low solubility and fast clearance from human plasma. The absence of structural information hampered the improvement of aphidicolin-like inhibitors: more than 50 modifications have been generated so far, but all have lost the inhibitory and antitumor properties. Here we report the crystal structure of the catalytic core of human DNA polymerase alpha (Pol alpha) in the ternary complex with an RNA-primed DNA template and aphidicolin. The inhibitor blocks binding of dCTP by docking at the Pol alpha active site and by rotating the template guanine. The structure provides a plausible mechanism for the selectivity of aphidicolin incorporation opposite template guanine and explains why previous modifications of aphidicolin failed to improve its affinity for Pol alpha. With new structural information, aphidicolin becomes an attractive lead compound for the design of novel derivatives with enhanced inhibitory properties for B-family DNA polymerases.

Structural basis for inhibition of DNA replication by aphidicolin.,Baranovskiy AG, Babayeva ND, Suwa Y, Gu J, Pavlov YI, Tahirov TH Nucleic Acids Res. 2014 Nov 27. pii: gku1209. PMID:25429975^[2]

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

References

↑ Dantzer F, Nasheuer HP, Vonesch JL, de Murcia G, Menissier-de Murcia J. Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication. Nucleic Acids Res. 1998 Apr 15;26(8):1891-8. PMID:9518481
↑ Baranovskiy AG, Babayeva ND, Suwa Y, Gu J, Pavlov YI, Tahirov TH. Structural basis for inhibition of DNA replication by aphidicolin. Nucleic Acids Res. 2014 Nov 27. pii: gku1209. PMID:25429975 doi:http://dx.doi.org/10.1093/nar/gku1209

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/4q5v"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic core of human DNA polymerase alpha in ternary complex with an RNA-primed DNA template and aphidicolin==
-<StructureSection load='4q5v' size='340' side='right' caption='[[4q5v]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
+<StructureSection load='4q5v' size='340' side='right'caption='[[4q5v]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4q5v]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q5V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q5V FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4q5v]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q5V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q5V FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2ZE:(3R,4R,4AR,6AS,8R,9R,11AS,11BS)-4,9-BIS(HYDROXYMETHYL)-4,11B-DIMETHYLTETRADECAHYDRO-8,11A-METHANOCYCLOHEPTA[A]NAPHTHALENE-3,9-DIOL'>2ZE</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POLA1, POLA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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 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=4q5v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q5v OCA], [http://pdbe.org/4q5v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4q5v RCSB], [http://www.ebi.ac.uk/pdbsum/4q5v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4q5v ProSAT]</span></td></tr>
@@ Line 27: / Line 28: @@
 </StructureSection>
 [[Category: DNA-directed DNA polymerase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Babayeva, N D]]
 [[Category: Baranovskiy, A G]]

4q5v

From Proteopedia

Revision as of 09:10, 24 April 2019

Crystal structure of the catalytic core of human DNA polymerase alpha in ternary complex with an RNA-primed DNA template and aphidicolin

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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