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| | ==Crystal structure of RPA70N in complex with a 3,4 dichlorophenylalanine ATRIP derived peptide== | | ==Crystal structure of RPA70N in complex with a 3,4 dichlorophenylalanine ATRIP derived peptide== |
| - | <StructureSection load='4nb3' size='340' side='right' caption='[[4nb3]], [[Resolution|resolution]] 1.35Å' scene=''> | + | <StructureSection load='4nb3' size='340' side='right'caption='[[4nb3]], [[Resolution|resolution]] 1.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4nb3]] is a 4 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=4NB3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NB3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4nb3]] is a 4 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=4NB3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NB3 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=2N2:2-(3,6-DIHYDROXY-9H-XANTHEN-9-YL)-5-{[(6-OXOHEXYL)CARBAMOTHIOYL]AMINO}BENZOIC+ACID'>2N2</scene>, <scene name='pdbligand=ZCL:3,4-DICHLORO-L-PHENYLALANINE'>ZCL</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2N2:2-(3,6-DIHYDROXY-9H-XANTHEN-9-YL)-5-{[(6-OXOHEXYL)CARBAMOTHIOYL]AMINO}BENZOIC+ACID'>2N2</scene>, <scene name='pdbligand=ZCL:3,4-DICHLORO-L-PHENYLALANINE'>ZCL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RPA1, REPA1, RPA70 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4nb3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nb3 OCA], [https://pdbe.org/4nb3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nb3 RCSB], [https://www.ebi.ac.uk/pdbsum/4nb3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nb3 ProSAT]</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=4nb3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nb3 OCA], [http://pdbe.org/4nb3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nb3 RCSB], [http://www.ebi.ac.uk/pdbsum/4nb3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4nb3 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Single-stranded DNA-binding protein|Single-stranded DNA-binding protein]] | + | *[[Single-stranded DNA-binding protein 3D structures|Single-stranded DNA-binding protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Chazin, W J]] | + | [[Category: Large Structures]] |
| - | [[Category: Cortez, D]] | + | [[Category: Chazin WJ]] |
| - | [[Category: Feldkamp, M D]] | + | [[Category: Cortez D]] |
| - | [[Category: Fesik, S W]] | + | [[Category: Feldkamp MD]] |
| - | [[Category: Frank, A O]] | + | [[Category: Fesik SW]] |
| - | [[Category: Luzwik, J W]] | + | [[Category: Frank AO]] |
| - | [[Category: Olejniczak, O T]] | + | [[Category: Luzwik JW]] |
| - | [[Category: Rossanese, O W]] | + | [[Category: Olejniczak OT]] |
| - | [[Category: Souza-Fagundes, E M]] | + | [[Category: Rossanese OW]] |
| - | [[Category: Vangamudi, B]] | + | [[Category: Souza-Fagundes EM]] |
| - | [[Category: Waterson, A G]] | + | [[Category: Vangamudi B]] |
| - | [[Category: Dichlorophenylalanine]]
| + | [[Category: Waterson AG]] |
| - | [[Category: Ob fold]]
| + | |
| - | [[Category: Peptide binding protein]]
| + | |
| - | [[Category: Protein-protein interaction]]
| + | |
| Structural highlights
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
Stapled helix peptides can serve as useful tools for inhibiting protein-protein interactions but can be difficult to optimize for affinity. Here we describe the discovery and optimization of a stapled helix peptide that binds to the N-terminal domain of the 70 kDa subunit of replication protein A (RPA70N). In addition to applying traditional optimization strategies, we employed a novel approach for efficiently designing peptides containing unnatural amino acids. We discovered hot spots in the target protein using a fragment-based screen, identified the amino acid that binds to the hot spot, and selected an unnatural amino acid to incorporate, based on the structure-activity relationships of small molecules that bind to this site. The resulting stapled helix peptide potently and selectively binds to RPA70N, does not disrupt ssDNA binding, and penetrates cells. This peptide may serve as a probe to explore the therapeutic potential of RPA70N inhibition in cancer.
Discovery of a Potent Stapled Helix Peptide That Binds to the 70N Domain of Replication Protein A.,Frank AO, Vangamudi B, Feldkamp MD, Souza-Fagundes EM, Luzwick JW, Cortez D, Olejniczak ET, Waterson AG, Rossanese OW, Chazin WJ, Fesik SW J Med Chem. 2014 Feb 19. PMID:24491171[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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, Vangamudi B, Feldkamp MD, Souza-Fagundes EM, Luzwick JW, Cortez D, Olejniczak ET, Waterson AG, Rossanese OW, Chazin WJ, Fesik SW. Discovery of a Potent Stapled Helix Peptide That Binds to the 70N Domain of Replication Protein A. J Med Chem. 2014 Feb 19. PMID:24491171 doi:http://dx.doi.org/10.1021/jm401730y
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