1q2p
From Proteopedia
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| - | + | {{STRUCTURE_1q2p| PDB=1q2p | SCENE= }} | |
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'''SHV-1 class A beta-lactamase complexed with penem WAY185229''' | '''SHV-1 class A beta-lactamase complexed with penem WAY185229''' | ||
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[[Category: Nukaga, M.]] | [[Category: Nukaga, M.]] | ||
[[Category: Venkatesan, A M.]] | [[Category: Venkatesan, A M.]] | ||
| - | [[Category: | + | [[Category: Beta-lactam antibiotic]] |
| - | [[Category: | + | [[Category: Drug design]] |
| - | [[Category: | + | [[Category: Hydrolase]] |
| - | [[Category: | + | [[Category: Inhibition]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 05:47:24 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 02:47, 3 May 2008
SHV-1 class A beta-lactamase complexed with penem WAY185229
Overview
The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine beta-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. In combination with piperacillin, their in vitro activities enhanced susceptibility of all class C resistant strains from various bacteria. Crystallographic structures of a serine-bound reaction intermediate of 17 with the class A SHV-1 and class C GC1 enzymes have been established to resolutions of 2.0 and 1.4 A, respectively, and refined to R-factors equal 0.163 and 0.145. In both beta-lactamases, a seven-membered 1,4-thiazepine ring has formed. The stereogenic C7 atom in the ring has the R configuration in the SHV-1 intermediate and has both R and S configurations in the GC1 intermediate. Hydrophobic stacking interactions between the tricyclic C7 substituent and a tyrosine side chain, rather than electrostatic or hydrogen bonding by the C3 carboxylic acid group, dominate in both complexes. The formation of the 1,4- thiazepine ring structures is proposed based on a 7-endo-trig cyclization.
About this Structure
1Q2P is a Single protein structure of sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA.
Reference
Structure-activity relationship of 6-methylidene penems bearing tricyclic heterocycles as broad-spectrum beta-lactamase inhibitors: crystallographic structures show unexpected binding of 1,4-thiazepine intermediates., Venkatesan AM, Gu Y, Dos Santos O, Abe T, Agarwal A, Yang Y, Petersen PJ, Weiss WJ, Mansour TS, Nukaga M, Hujer AM, Bonomo RA, Knox JR, J Med Chem. 2004 Dec 16;47(26):6556-68. PMID:15588091 Page seeded by OCA on Sat May 3 05:47:24 2008
