Synergistic effects of substrate-induced conformational changes in phosphoglycerate kinase activation

Bradley E. Bernstein, Paul A. M. Michels and Wim G. J. Hol
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Bradley E. Bernstein: University of Washington
Paul A. M. Michels: University ofLouvain
Wim G. J. Hol: University of Washington

Nature, 1997, vol. 385, issue 6613, 275-278

Abstract: Abstract Phosphoglycerate kinase (PGK), a key enzyme in glycolysis, catalyses the transfer of a phosphoryl-group from 1,3-bis-phosphoglycerate to ADP to form 3-phosphoglycerate and ATP. Despite extensive kinetic and structural investigations over more than two decades, the conformation assumed by this enzyme during catalysis remained unknown. Here we present the 2.8 Å crystal structure of a ternary complex of PGK from Trypanosoma brucei, the causative agent of sleeping sickness. This structure determination relied on a procedure in which fragments containing less than 10% of the scattering mass were successively positioned in the unit cell to obtain phases. The PGK ternary complex exhibits a dramatic closing of the large cleft between the two domains seen in all previous studies1–6, thereby bringing the two ligands, 3-phosphoglycerate and ADP into close proximity. Our results demonstrate that PGK is a hinge-bending enzyme, reveal a novel mechanism in which substrate-induced effects combine synergistically to induce major conformational changes and, to our knowledge, afford the first observation of the PGK active site in a catalytic conformation.

Date: 1997
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DOI: 10.1038/385275a0

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