8c3n: Difference between revisions

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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8c3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8c3n OCA], [https://pdbe.org/8c3n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8c3n RCSB], [https://www.ebi.ac.uk/pdbsum/8c3n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8c3n ProSAT]</span></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=8c3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8c3n OCA], [https://pdbe.org/8c3n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8c3n RCSB], [https://www.ebi.ac.uk/pdbsum/8c3n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8c3n ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/BRCA2_HUMAN BRCA2_HUMAN] Defects in BRCA2 are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case.<ref>PMID:16793542</ref> <ref>PMID:8640237</ref> <ref>PMID:9150152</ref> <ref>PMID:9654203</ref> <ref>PMID:9609997</ref> <ref>PMID:9971877</ref> <ref>PMID:10399947</ref> <ref>PMID:10978364</ref> <ref>PMID:11139248</ref> <ref>PMID:11241844</ref> <ref>PMID:12145750</ref> <ref>PMID:12373604</ref> <ref>PMID:12442274</ref> <ref>PMID:12442275</ref> <ref>PMID:11948477</ref> <ref>PMID:12938098</ref> <ref>PMID:15026808</ref> <ref>PMID:15172753</ref> <ref>PMID:14722926</ref> <ref>PMID:15365993</ref>  Defects in BRCA2 are the cause of pancreatic cancer type 2 (PNCA2) [MIM:[https://omim.org/entry/613347 613347]. It is a malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.<ref>PMID:9140390</ref>  Defects in BRCA2 are a cause of susceptibility to familial breast-ovarian cancer type 2 (BROVCA2) [MIM:[https://omim.org/entry/612555 612555]. A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate.  Defects in BRCA2 are the cause of Fanconi anemia complementation group D type 1 (FANCD1) [MIM:[https://omim.org/entry/605724 605724]. It is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.<ref>PMID:12065746</ref> <ref>PMID:14670928</ref> <ref>PMID:16825431</ref>  Defects in BRCA2 are a cause of glioma type 3 (GLM3) [MIM:[https://omim.org/entry/613029 613029]. Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes.<ref>PMID:15689453</ref>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/BRCA2_HUMAN BRCA2_HUMAN] Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. In concert with NPM1, regulates centrosome duplication.<ref>PMID:15115758</ref> <ref>PMID:15199141</ref> <ref>PMID:15671039</ref> <ref>PMID:18317453</ref> <ref>PMID:20729859</ref> <ref>PMID:20729858</ref> <ref>PMID:20729832</ref> <ref>PMID:21084279</ref>  
[https://www.uniprot.org/uniprot/RADA_PYRFU RADA_PYRFU] Involved in DNA repair and in homologous recombination. Binds and assemble on single-stranded DNA to form a nucleoprotein filament. Hydrolyzes ATP in a ssDNA-dependent manner and promotes DNA strand exchange between homologous DNA molecules.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Stapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinyl-heteroaryl chemistry as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeat-derived inhibitors of the RAD51 recombinase, showing that a diverse range of secondary structure elements in the BRC repeat can be stapled without compromising binding and function. Using X-ray crystallography, we elucidate the atomic-level features of the staple moieties. We then demonstrate that BRC-repeat-derived stapled peptides can disrupt RAD51 function in cells following ionising radiation treatment.
 
A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase.,Pantelejevs T, Zuazua-Villar P, Koczy O, Counsell AJ, Walsh SJ, Robertson NS, Spring DR, Downs JA, Hyvonen M Chem Sci. 2023 Nov 21;14(47):13915-13923. doi: 10.1039/d3sc03331g. eCollection , 2023 Dec 6. PMID:38075664<ref>PMID:38075664</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8c3n" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Latest revision as of 14:58, 23 October 2024

Stapled peptide SP30 in complex with humanised RadA mutant HumRadA22Stapled peptide SP30 in complex with humanised RadA mutant HumRadA22

Structural highlights

8c3n is a 2 chain structure with sequence from Homo sapiens and Pyrococcus furiosus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.21Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RADA_PYRFU Involved in DNA repair and in homologous recombination. Binds and assemble on single-stranded DNA to form a nucleoprotein filament. Hydrolyzes ATP in a ssDNA-dependent manner and promotes DNA strand exchange between homologous DNA molecules.

Publication Abstract from PubMed

Stapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinyl-heteroaryl chemistry as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeat-derived inhibitors of the RAD51 recombinase, showing that a diverse range of secondary structure elements in the BRC repeat can be stapled without compromising binding and function. Using X-ray crystallography, we elucidate the atomic-level features of the staple moieties. We then demonstrate that BRC-repeat-derived stapled peptides can disrupt RAD51 function in cells following ionising radiation treatment.

A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase.,Pantelejevs T, Zuazua-Villar P, Koczy O, Counsell AJ, Walsh SJ, Robertson NS, Spring DR, Downs JA, Hyvonen M Chem Sci. 2023 Nov 21;14(47):13915-13923. doi: 10.1039/d3sc03331g. eCollection , 2023 Dec 6. PMID:38075664[1]

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

References

  1. ↑ Pantelejevs T, Zuazua-Villar P, Koczy O, Counsell AJ, Walsh SJ, Robertson NS, Spring DR, Downs JA, Hyvönen M. A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase. Chem Sci. 2023 Nov 21;14(47):13915-13923. PMID:38075664 doi:10.1039/d3sc03331g

8c3n, resolution 1.21Å

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