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==Fragment-Based Discovery of a Potent Inhibitor of Replication Protein A Protein-Protein Interactions==
<StructureSection load='4lwc' size='340' side='right'caption='[[4lwc]], [[Resolution|resolution]] 1.61&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4lwc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LWC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LWC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.61&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1XU:5-[3-CHLORO-4-({4-[1-(3,4-DICHLOROPHENYL)-1H-PYRAZOL-5-YL]BENZYL}CARBAMOTHIOYL)PHENYL]FURAN-2-CARBOXYLIC+ACID'>1XU</scene></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=4lwc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lwc OCA], [https://pdbe.org/4lwc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lwc RCSB], [https://www.ebi.ac.uk/pdbsum/4lwc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lwc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RFA1_HUMAN RFA1_HUMAN] Plays an essential role in several cellular processes in DNA metabolism including replication, recombination and DNA repair. Binds and subsequently stabilizes single-stranded DNA intermediates and thus prevents complementary DNA from reannealing.<ref>PMID:19116208</ref> <ref>PMID:19996105</ref>   Functions as component of the alternative replication protein A complex (aRPA). aRPA binds single-stranded DNA and probably plays a role in DNA repair; it does not support chromosomal DNA replication and cell cycle progression through S-phase. In vitro, aRPA cannot promote efficient priming by DNA polymerase alpha but supports DNA polymerase delta synthesis in the presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange.<ref>PMID:19116208</ref> <ref>PMID:19996105</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Replication protein A (RPA), the major eukaryotic single-stranded DNA (ssDNA)-binding protein, is involved in nearly all cellular DNA transactions. The RPA N-terminal domain (RPA70N) is a recruitment site for proteins involved in DNA-damage response and repair. Selective inhibition of these protein-protein interactions has the potential to inhibit the DNA-damage response and to sensitize cancer cells to DNA-damaging agents without affecting other functions of RPA. To discover a potent, selective inhibitor of the RPA70N protein-protein interactions to test this hypothesis, we used NMR spectroscopy to identify fragment hits that bind to two adjacent sites in the basic cleft of RPA70N. High-resolution X-ray crystal structures of RPA70N-ligand complexes revealed how these fragments bind to RPA and guided the design of linked compounds that simultaneously occupy both sites. We have synthesized linked molecules that bind to RPA70N with submicromolar affinity and minimal disruption of RPA's interaction with ssDNA.

Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach.,Frank AO, Feldkamp MD, Kennedy JP, Waterson AG, Pelz NF, Patrone JD, Vangamudi B, Camper DV, Rossanese OW, Chazin WJ, Fesik SW J Med Chem. 2013 Nov 27;56(22):9242-50. doi: 10.1021/jm401333u. Epub 2013 Nov 11. PMID:24147804<ref>PMID:24147804</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4lwc" style="background-color:#fffaf0;"></div>

==See Also==
*[[Single-stranded DNA-binding protein 3D structures|Single-stranded DNA-binding protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Camper DV]]
[[Category: Chazin WJ]]
[[Category: Feldkamp MD]]
[[Category: Fesik SW]]
[[Category: Frank AO]]
[[Category: Kennedy JP]]
[[Category: Olejnczak EO]]
[[Category: Patrone JD]]
[[Category: Pelz NF]]
[[Category: Rossanese OW]]
[[Category: Vangamudi B]]
[[Category: Waterson AG]]