PDBsum entry: 1q2q

Hydrolase

PDB id: 1q2q

Contents

Protein chain

359 a.a. *

Ligands

WY2

GOL

Waters ×452

* Residue conservation analysis

PDB id:

1q2q

Name:

Hydrolase

Title:

Enterobacter cloacae gc1 class c beta-lactamase complexed wi way185229

Structure:

Class c beta-lactamase. Chain: a. Fragment: penicillinase. Synonym: beta-lactamase ampcpit-2. Engineered: yes

Source:

Enterobacter cloacae. Organism_taxid: 550. Gene: bla. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.40Å R-factor: 0.145 R-free: 0.209

Authors:

M.Nukaga,A.M.Venkatesan,T.S.Mansour,A.Hujer,R.A.Bonomo,J.R.K

Key ref:

A.M.Venkatesan et al. (2004). 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. PubMed id: 15588091 DOI: 10.1021/jm049680x

Date:

25-Jul-03 Release date: 14-Sep-04

Protein chain

Q59401  (Q59401_ENTCL) -  Class C beta-lactamase (Precursor)

Seq: 384 a.a.

Struc: 359 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.2.6 - Beta-lactamase.
• Pathway: Penicillin Biosynthesis and Metabolism
• Reaction: A beta-lactam + H₂O = a substituted beta-amino acid
• Cofactor: Zinc

 Gene Ontology (GO) functional annotation 

• Cellular component: outer membrane-bounded periplasmic space (1 term)
• Biological process: antibiotic catabolic process (1 term)
• Biochemical function: hydrolase activity (2 terms)

DOI no: 10.1021/jm049680x

J Med Chem 47:6556-6568 (2004)

PubMed id: 15588091

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.

A.M.Venkatesan, Y.Gu, O.Dos Santos, T.Abe, A.Agarwal, Y.Yang, P.J.Petersen, W.J.Weiss, T.S.Mansour, M.Nukaga, A.M.Hujer, R.A.Bonomo, J.R.Knox.

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.