Tyrosine 121 moves revealing a ligandable pocket that couples catalysis to ATP-binding in serine racemase

DOI: 10.1038/s42003-022-03264-5

Authors: Chloe R. Koulouris (University of Sussex) , Sian E. Gardiner (Cardiff University) , Tessa K. Harris (Cardiff University) , Karen T. Elvers (Cardiff University) , S. Mark Roe (University of Sussex) , Jason A. Gillespie (Cardiff University) , Simon E. Ward (Cardiff University) , Olivera Grubisha (Cardiff University) , Robert A. Nicholls (MRC Laboratory of Molecular Biology) , John R. Atack (Cardiff University) , Benjamin D. Bax (Cardiff University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 5

State: Published (Approved)
Published: April 2022
Diamond Proposal Number(s): 19990

Abstract: Human serine racemase (hSR) catalyses racemisation of L-serine to D-serine, the latter of which is a co-agonist of the NMDA subtype of glutamate receptors that are important in synaptic plasticity, learning and memory. In a ‘closed’ hSR structure containing the allosteric activator ATP, the inhibitor malonate is enclosed between the large and small domains while ATP is distal to the active site, residing at the dimer interface with the Tyr121 hydroxyl group contacting the α-phosphate of ATP. In contrast, in ‘open’ hSR structures, Tyr121 sits in the core of the small domain with its hydroxyl contacting the key catalytic residue Ser84. The ability to regulate SR activity by flipping Tyr121 from the core of the small domain to the dimer interface appears to have evolved in animals with a CNS. Multiple X-ray crystallographic enzyme-fragment structures show Tyr121 flipped out of its pocket in the core of the small domain. Data suggest that this ligandable pocket could be targeted by molecules that inhibit enzyme activity.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 18/04/2022 11:50

Documents:
s42003-022-03264-5.pdf

Discipline Tags:

Health & Wellbeing Neurology Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening