2FQ6

Cystathionine beta-lyase (cbl) from escherichia coli in complex with n-hydrazinocarbonylmethyl-2-trifluoromethyl-benzamide

Summary for 2FQ6

• Entry DOI: 10.2210/pdb2fq6/pdb
• Descriptor: Cystathionine beta-lyase, PHOSPHORIC ACID MONO-(5-HYDROXY-6-METHYL-4-{[2-(2-TRIFLUOROMETHYL-BENZOYLAMINO)-ACETYL]-HYDRAZONOMETHYL}-PYRIDIN-3-YLMETHYL)ESTER (3 entities in total)
• Functional Keywords: protein-inhibitor complex, plp cofactor covalently bound to p3f inhibitor, lyase
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P06721
• Total number of polymer chains: 2
• Total formula weight: 91845.91

Authors

Junop, M.S. (deposition date: 2006-01-17, release date: 2006-12-26, Last modification date: 2023-08-30)

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 (1.78 Å)