2GQN

Cystathionine Beta-Lyase (CBL) from Escherichia Coli in complex with N-Hydrazinocarbonylmethyl-2-Nitro-Benzamide

Summary for 2GQN

• Entry DOI: 10.2210/pdb2gqn/pdb
• Related: 2FQ6
• Descriptor: Cystathionine beta-lyase, (5-HYDROXY-6-METHYL-4-((2-(2-(2-NITROBENZAMIDO)ACETYL)HYDRAZINYL)METHYL)PYRIDIN-3-YL)METHYL DIHYDROGEN PHOSPHATE (3 entities in total)
• Functional Keywords: protein-inhibitor complex, plp cofactor covalently bount to blp inhibitor, lyase
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P06721
• Total number of polymer chains: 2
• Total formula weight: 91803.94

Authors

Summerfield, R.,Junop, M.S. (deposition date: 2006-04-21, release date: 2007-03-06, Last modification date: 2024-02-14)

Primary citation

Ejim, L.J.,Blanchard, J.E.,Koteva, K.P.,Sumerfield, R.,Elowe, N.H.,Chechetto, J.D.,Brown, E.D.,Junop, M.S.,Wright, G.D.
Inhibitors of Bacterial Cystathionine beta-Lyase: Leads for New Antimicrobial Agents and Probes of Enzyme Structure and Function.
J.Med.Chem., 50:755-764, 2007

PubMed Abstract: The biosynthesis of methionine is an attractive antibiotic target given its importance in protein and DNA metabolism and its absence in mammals. We have performed a high-throughput screen of the methionine biosynthesis enzyme cystathionine beta-lyase (CBL) against a library of 50 000 small molecules and have identified several compounds that inhibit CBL enzyme activity in vitro. These hit molecules were of two classes: those that blocked CBL activity with mixed steady-state inhibition and those that covalently interacted with the enzyme at the active site pyridoxal phosphate cofactor with slow-binding inhibition kinetics. We determined the crystal structure of one of the slow-binding inhibitors in complex with CBL and used this structure as a guide in the synthesis of a small, focused library of analogues, some of which had improved enzyme inhibition properties. These studies provide the first lead molecules for antimicrobial agents that target cystathionine beta-lyase in methionine biosynthesis.

PubMed: 17300162
DOI: 10.1021/jm061132r

Experimental method

X-RAY DIFFRACTION (1.8 Å)