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A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family

DOI: 10.1093/nar/gkab692 DOI Help

Authors: Hannah T. Baddock (University of Oxford) , Joseph A. Newman (University of Oxford) , Yuliana Yosaatmadja (University of Oxford) , Marcin Bielinski (University of Oxford) , Christopher J. Schofield (University of Oxford) , Opher Gileadi (University of Oxford) , Peter j. Mchugh (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 461

State: Published (Approved)
Published: August 2021
Diamond Proposal Number(s): 15433

Open Access Open Access

Abstract: The SNM1 nucleases which help maintain genome integrity are members of the metallo-β-lactamase (MBL) structural superfamily. Their conserved MBL-β-CASP-fold SNM1 core provides a molecular scaffold forming an active site which coordinates the metal ions required for catalysis. The features that determine SNM1 endo- versus exonuclease activity, and which control substrate selectivity and binding are poorly understood. We describe a structure of SNM1B/Apollo with two nucleotides bound to its active site, resembling the product state of its exonuclease reaction. The structure enables definition of key SNM1B residues that form contacts with DNA and identifies a 5′ phosphate binding pocket, which we demonstrate is important in catalysis and which has a key role in determining endo- versus exonucleolytic activity across the SNM1 family. We probed the capacity of SNM1B to digest past sites of common endogenous DNA lesions and find that base modifications planar to the nucleobase can be accommodated due to the open architecture of the active site, but lesions axial to the plane of the nucleobase are not well tolerated due to constriction around the altered base. We propose that SNM1B/Apollo might employ its activity to help remove common oxidative lesions from telomeres.

Diamond Keywords: Breast Cancer; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 17/08/2021 09:35

Documents:
gkab692.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Genetics Catalysis Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)