2fq6
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The biosynthesis of methionine is an attractive antibiotic target given | + | 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. |
==About this Structure== | ==About this Structure== | ||
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[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Junop, M | + | [[Category: Junop, M S.]] |
[[Category: P3F]] | [[Category: P3F]] | ||
[[Category: plp cofactor covalently bound to p3f inhibitor]] | [[Category: plp cofactor covalently bound to p3f inhibitor]] | ||
[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:24:01 2008'' |
Revision as of 15:24, 21 February 2008
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Cystathionine beta-lyase (cbl) from escherichia coli in complex with n-hydrazinocarbonylmethyl-2-trifluoromethyl-benzamide
Overview
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.
About this Structure
2FQ6 is a Single protein structure of sequence from Escherichia coli with as ligand. Active as Cystathionine beta-lyase, with EC number 4.4.1.8 Full crystallographic information is available from OCA.
Reference
Inhibitors of bacterial cystathionine beta-lyase: leads for new antimicrobial agents and probes of enzyme structure and function., Ejim LJ, Blanchard JE, Koteva KP, Sumerfield R, Elowe NH, Chechetto JD, Brown ED, Junop MS, Wright GD, J Med Chem. 2007 Feb 22;50(4):755-64. PMID:17300162
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