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

By Chloe R. Koulouris, Sian E. Gardiner, Tessa K. Harris, Karen T Elvers, S. Mark Roe, Jason A. Gillespie, Simon E. Ward, Olivera Grubisha, Robert A. Nicholls, John R. Atack, Benjamin D. Bax

Posted 15 Feb 2021
bioRxiv DOI: 10.1101/2021.02.12.430960

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 ATP a-phosphate. 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 enzymefragment structures show that Tyr121 is flipped out of its pocket, suggesting that this pocket is druggable.

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