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4lwc

From Proteopedia

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Current revision

Fragment-Based Discovery of a Potent Inhibitor of Replication Protein A Protein-Protein Interactions

Structural highlights

4lwc is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.61Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] 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.^[3] ^[4]

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^[5]

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

References

↑ Mason AC, Haring SJ, Pryor JM, Staloch CA, Gan TF, Wold MS. An alternative form of replication protein a prevents viral replication in vitro. J Biol Chem. 2009 Feb 20;284(8):5324-31. doi: 10.1074/jbc.M808963200. Epub 2008, Dec 29. PMID:19116208 doi:10.1074/jbc.M808963200
↑ Kemp MG, Mason AC, Carreira A, Reardon JT, Haring SJ, Borgstahl GE, Kowalczykowski SC, Sancar A, Wold MS. An alternative form of replication protein a expressed in normal human tissues supports DNA repair. J Biol Chem. 2010 Feb 12;285(7):4788-97. doi: 10.1074/jbc.M109.079418. Epub 2009 , Dec 7. PMID:19996105 doi:10.1074/jbc.M109.079418
↑ Mason AC, Haring SJ, Pryor JM, Staloch CA, Gan TF, Wold MS. An alternative form of replication protein a prevents viral replication in vitro. J Biol Chem. 2009 Feb 20;284(8):5324-31. doi: 10.1074/jbc.M808963200. Epub 2008, Dec 29. PMID:19116208 doi:10.1074/jbc.M808963200
↑ Kemp MG, Mason AC, Carreira A, Reardon JT, Haring SJ, Borgstahl GE, Kowalczykowski SC, Sancar A, Wold MS. An alternative form of replication protein a expressed in normal human tissues supports DNA repair. J Biol Chem. 2010 Feb 12;285(7):4788-97. doi: 10.1074/jbc.M109.079418. Epub 2009 , Dec 7. PMID:19996105 doi:10.1074/jbc.M109.079418
↑ Frank AO, Feldkamp MD, Kennedy JP, Waterson AG, Pelz NF, Patrone JD, Vangamudi B, Camper DV, Rossanese OW, Chazin WJ, Fesik SW. Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach. J Med Chem. 2013 Nov 27;56(22):9242-50. doi: 10.1021/jm401333u. Epub 2013 Nov 11. PMID:24147804 doi:http://dx.doi.org/10.1021/jm401333u

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/4lwc"

@@ Line 4: / Line 4: @@
 == 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='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>
+</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>

4lwc

From Proteopedia

Current revision

Fragment-Based Discovery of a Potent Inhibitor of Replication Protein A Protein-Protein Interactions

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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