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Identifying small molecule binding sites for epigenetic proteins at domain-domain interfaces

DOI: 10.1002/cmdc.201800030 DOI Help

Authors: Paul Brennan (Structural Genomics Consortium, University of Oxford) , David Bowkett (Structural Genomics Consortium, University of Oxford) , Romain Talon (University of Oxford) , Cynthia Tallant (Structural Genomics Consortium, University of Oxford, U.K.) , Chris Schofield (University of Oxford) , Gordon Bruton (GlaxoSmithKline) , Frank Von Delft (Diamond Light Source; University of Johannesburg) , Stefan Knapp (Structural Genomics Consortium, University of Oxford; Johann Wolfgang Goethe-University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chemmedchem

State: Published (Approved)
Published: March 2018

Open Access Open Access

Abstract: Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain‐domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognizing and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain‐domain interfaces. For the tandem plant homeodomain‐bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.

Journal Keywords: Epigenetics; Histones; Bromodomains; Tudor domains; PHD domains; MBT domains; PWWP domains; SiteMap; X-ray fragment screening; SP100C

Diamond Keywords: Epigenetics

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 11/04/2018 12:19


Discipline Tags:

Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)