2c6c

From Proteopedia

Revision as of 17:01, 18 December 2007

MEMBRANE-BOUND GLUTAMATE CARBOXYPEPTIDASE II (GCPII) IN COMPLEX WITH GPI-18431 (S)-2-(4-IODOBENZYLPHOSPHONOMETHYL)-PENTANEDIOIC ACID

Overview

Membrane-bound glutamate carboxypeptidase II (GCPII) is a zinc, metalloenzyme that catalyzes the hydrolysis of the neurotransmitter, N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and, L-glutamate (which is itself a neurotransmitter). Potent and selective, GCPII inhibitors have been shown to decrease brain glutamate and provide, neuroprotection in preclinical models of stroke, amyotrophic lateral, sclerosis, and neuropathic pain. Here, we report crystal structures of the, extracellular part of GCPII in complex with both potent and weak, inhibitors and with glutamate, the product of the enzyme's hydrolysis, reaction, at 2.0, 2.4, and 2.2 A resolution, respectively. GCPII folds, into three domains: protease-like, apical, and C-terminal. All three, participate in substrate binding, with two of them directly involved in, C-terminal glutamate recognition. One of the carbohydrate moieties of the, enzyme is essential for homodimer formation of GCPII. The, three-dimensional structures presented here reveal an induced-fit, substrate-binding mode of this key enzyme and provide essential, information for the design of GCPII inhibitors useful in the treatment of, neuronal diseases and prostate cancer.

Disease

Known diseases associated with this structure: Myocardial infarcation, susceptibility to OMIM:[602855]

About this Structure

2C6C is a Single protein structure of sequence from Homo sapiens with NAG, ZN, CA, CL and 24I as ligands. Active as Glutamate carboxypeptidase II, with EC number 3.4.17.21 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer., Mesters JR, Barinka C, Li W, Tsukamoto T, Majer P, Slusher BS, Konvalinka J, Hilgenfeld R, EMBO J. 2006 Mar 22;25(6):1375-84. Epub 2006 Feb 9. PMID:16467855

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