1Q2Q

Enterobacter cloacae GC1 class C beta-lactamase complexed with penem WAY185229

Summary for 1Q2Q

• Entry DOI: 10.2210/pdb1q2q/pdb
• Related: 1ONG 1ONH 1Q2P 1SHV
• Descriptor: class C beta-lactamase, (6,7-DIHYDRO-5H-CYCLOPENTA[D]IMIDAZO[2,1-B]THIAZOL-2-YL]-4,7-DIHYDRO[1,4]THIAZEPINE-3,6-DICARBOXYLIC ACID, GLYCEROL, ... (4 entities in total)
• Functional Keywords: hydrolase, inhibition, beta-lactam antibiotics, drug design
• Biological source: Enterobacter cloacae
• Total number of polymer chains: 1
• Total formula weight: 39963.57

Authors

Nukaga, M.,Venkatesan, A.M.,Mansour, T.S.,Hujer, A.,Bonomo, R.A.,Knox, J.R. (deposition date: 2003-07-25, release date: 2004-09-14, Last modification date: 2023-08-16)

Primary citation

Venkatesan, A.M.,Gu, Y.,Dos Santos, O.,Abe, T.,Agarwal, A.,Yang, Y.,Petersen, P.J.,Weiss, W.J.,Mansour, T.S.,Nukaga, M.,Hujer, A.,Bonomo, R.A.,Knox, J.R.
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
J.Med.Chem., 47:6556-6568, 2004

PubMed Abstract: 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.

PubMed: 15588091
DOI: 10.1021/jm049680x

Experimental method

X-RAY DIFFRACTION (1.4 Å)