8TBS

Structure of human erythrocyte pyruvate kinase in complex with an allosteric activator AG-946

Summary for 8TBS

• Entry DOI: 10.2210/pdb8tbs/pdb
• Descriptor: Pyruvate kinase PKLR, 1,6-di-O-phosphono-beta-D-fructofuranose, MANGANESE (II) ION, ... (7 entities in total)
• Functional Keywords: erythrocyte pyruvate kinase, pkr, pklr, allosteric activator, glycolysis, transferase, transferase-activator complex, transferase/activator
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 474990.68

Authors

Jin, L.,Padyana, A. (deposition date: 2023-06-29, release date: 2023-12-27, Last modification date: 2024-03-20)

Primary citation

Liu, T.,Padyana, A.K.,Judd, E.T.,Jin, L.,Hammoudeh, D.,Kung, C.,Dang, L.
Structure-Based Design of AG-946, a Pyruvate Kinase Activator.
Chemmedchem, 19:e202300559-e202300559, 2024

PubMed Abstract: Pyruvate kinase (PK) is the enzyme that catalyzes the conversion of phosphoenolpyruvate and adenosine diphosphate to pyruvate and adenosine triphosphate in glycolysis and plays a crucial role in regulating cell metabolism. We describe the structure-based design of AG-946, an activator of PK isoforms, including red blood cell-specific forms of PK (PKR). This was designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency toward PKR while reducing activity against off-targets observed from the original scaffold. AG-946 (1) demonstrated activation of human wild-type PK (half-maximal activation concentration [AC ]=0.005 μM) and a panel of mutated PK proteins (K410E [AC =0.0043 μM] and R510Q [AC =0.0069 μM]), (2) displayed a significantly longer half-time of activation (>150-fold) compared with 6-(3-methoxybenzyl)-4-methyl-2-(methylsulfinyl)-4,6-dihydro-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one, and (3) stabilized PKR R510Q, an unstable mutant PKR enzyme, and preserved its catalytic activity under increasingly denaturing conditions. As a potent, oral, small-molecule allosteric activator of wild-type and mutant PKR, AG-946 was advanced to human clinical trials.

PubMed: 38109501
DOI: 10.1002/cmdc.202300559

Experimental method

X-RAY DIFFRACTION (2.35 Å)