title: Structure of human Bloom's syndrome helicase in complex with ADP and duplex DNA.
abstract: Bloom's syndrome is an autosomal recessive genome-instability disorder associated with a predisposition to cancer, premature aging and developmental abnormalities. It is caused by mutations that inactivate the DNA helicase activity of the BLM protein or nullify protein expression. The BLM helicase has been implicated in the alternative lengthening of telomeres (ALT) pathway, which is essential for the limitless replication of some cancer cells. This pathway is used by 10-15% of cancers, where inhibitors of BLM are expected to facilitate telomere shortening, leading to apoptosis or senescence. Here, the crystal structure of the human BLM helicase in complex with ADP and a 3'-overhang DNA duplex is reported. In addition to the helicase core, the BLM construct used for crystallization (residues 640-1298) includes the RecQ C-terminal (RQC) and the helicase and ribonuclease D C-terminal (HRDC) domains. Analysis of the structure provides detailed information on the interactions of the protein with DNA and helps to explain the mechanism coupling ATP hydrolysis and DNA unwinding. In addition, mapping of the missense mutations onto the structure provides insights into the molecular basis of Bloom's syndrome.
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Swan
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Valerie
authors.initials: V
authors.lastname: Legris
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Adam
authors.initials: A
authors.lastname: Tanner
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Reaper
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vial
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bordas
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: John R
authors.initials: JR
authors.lastname: Pollard
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Charlton
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Julian M C
authors.initials: JM
authors.lastname: Golec
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, England.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Bertrand
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D001816:Bloom Syndrome / Q000235:genetics; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D009154:Mutation; D009692:Nucleic Acid Heteroduplexes; D011487:Protein Conformation; D053484:RecQ Helicases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D009692:Nucleic Acid Heteroduplexes; D000244:Adenosine Diphosphate; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: BLM; Bloom's syndrome; DNA helicases