7auc

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Crystal structure of an engineered helicase domain construct for human Bloom syndrome protein (BLM)

Structural highlights

7auc 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 1.53Å
Ligands:ACT, ADP, CA, EDO, GOL, MG, PG4, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BLM_HUMAN Bloom syndrome. The disease is caused by mutations affecting the gene represented in this entry.

Function

BLM_HUMAN Participates in DNA replication and repair. Exhibits a magnesium-dependent ATP-dependent DNA-helicase activity that unwinds single- and double-stranded DNA in a 3'-5' direction. Involved in 5'-end resection of DNA during double-strand break (DSB) repair: unwinds DNA and recruits DNA2 which mediates the cleavage of 5'-ssDNA. Negatively regulates sister chromatid exchange (SCE).[1] [2] [3] [4]

Publication Abstract from PubMed

BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response; however, selective small molecule inhibitors of defined mechanism are currently lacking. Here, we identify and characterise a specific inhibitor of BLM's ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.

Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein.,Chen X, Ali YI, Fisher CE, Arribas-Bosacoma R, Rajasekaran MB, Williams G, Walker S, Booth JR, Hudson JJ, Roe SM, Pearl LH, Ward SE, Pearl FM, Oliver AW Elife. 2021 Mar 1;10. pii: 65339. doi: 10.7554/eLife.65339. PMID:33647232[5]

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

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Citations
2 reviews cite this structure
AlphaFold, Artificial Intelligence (AI), and Allostery.
Nussinov et al. (2022)
1 more
6 other articles
No citations found

See Also

References

  1. ↑ Karow JK, Chakraverty RK, Hickson ID. The Bloom's syndrome gene product is a 3'-5' DNA helicase. J Biol Chem. 1997 Dec 5;272(49):30611-4. PMID:9388193
  2. ↑ Langland G, Elliott J, Li Y, Creaney J, Dixon K, Groden J. The BLM helicase is necessary for normal DNA double-strand break repair. Cancer Res. 2002 May 15;62(10):2766-70. PMID:12019152
  3. ↑ Nimonkar AV, Genschel J, Kinoshita E, Polaczek P, Campbell JL, Wyman C, Modrich P, Kowalczykowski SC. BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev. 2011 Feb 15;25(4):350-62. doi: 10.1101/gad.2003811. PMID:21325134 doi:http://dx.doi.org/10.1101/gad.2003811
  4. ↑ Wan L, Han J, Liu T, Dong S, Xie F, Chen H, Huang J. Scaffolding protein SPIDR/KIAA0146 connects the Bloom syndrome helicase with homologous recombination repair. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10646-51. doi:, 10.1073/pnas.1220921110. Epub 2013 Mar 18. PMID:23509288 doi:http://dx.doi.org/10.1073/pnas.1220921110
  5. ↑ Chen X, Ali YI, Fisher CE, Arribas-Bosacoma R, Rajasekaran MB, Williams G, Walker S, Booth JR, Hudson JJ, Roe SM, Pearl LH, Ward SE, Pearl FM, Oliver AW. Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein. Elife. 2021 Mar 1;10. pii: 65339. doi: 10.7554/eLife.65339. PMID:33647232 doi:http://dx.doi.org/10.7554/eLife.65339

Contents


PDB ID 7auc

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OCA

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