Discovery of allosteric binding sites by crystallographic fragment screening

DOI: 10.1016/j.sbi.2020.08.004

Authors: Tobias Krojer (Structural Genomics Consortium, University of Oxford) , James S. Fraser (University of California San Francisco) , Frank Von Delft (Structural Genomics Consortium, University of Oxford; Diamond Light Source; Research Complex at Harwell; University of Johannesburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Current Opinion In Structural Biology , VOL 65 , PAGES 209 - 216

State: Published (Approved)
Published: December 2020

Abstract: Understanding allosteric regulation of proteins is fundamental to our study of protein structure and function. Moreover, allosteric binding pockets have become a major target of drug discovery efforts in recent years. However, even though the function of almost every protein can be influenced by allostery, it remains a challenge to discover, rationalise and validate putative allosteric binding pockets. This review examines how the discovery and analysis of putative allosteric binding sites have been influenced by the availability of centralised facilities for crystallographic fragment screening, along with newly developed computational methods for modelling low occupancy features. We discuss the experimental parameters required for success, and how new methods could influence the field in the future. Finally, we reflect on the general problem of how to translate these findings into actual ligand development programs.

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: XChem
Instruments: