4O33

Crystal Structure of human PGK1 3PG and terazosin(TZN) ternary complex

Summary for 4O33

• Entry DOI: 10.2210/pdb4o33/pdb
• Related: 4O3F
• Descriptor: Phosphoglycerate kinase 1, [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl][(2R)-tetrahydrofuran-2-yl]methanone, 3-PHOSPHOGLYCERIC ACID, ... (4 entities in total)
• Functional Keywords: enzyme-drug complex, transferase-transferase activitor complex, transferase-transferase activator complex, transferase/transferase activator
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00558
• Total number of polymer chains: 1
• Total formula weight: 45234.06

Authors

Li, X.L.,Finci, L.I.,Wang, J.H. (deposition date: 2013-12-18, release date: 2014-10-29, Last modification date: 2023-09-20)

Primary citation

Chen, X.,Zhao, C.,Li, X.,Wang, T.,Li, Y.,Cao, C.,Ding, Y.,Dong, M.,Finci, L.,Wang, J.H.,Li, X.,Liu, L.
Terazosin activates Pgk1 and Hsp90 to promote stress resistance.
Nat.Chem.Biol., 11:19-25, 2015

PubMed Abstract: Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed α1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline's ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.

PubMed: 25383758
DOI: 10.1038/nchembio.1657

Experimental method

X-RAY DIFFRACTION (2.1 Å)