PDBsum entry: 1m2x

Hydrolase

PDB id: 1m2x

Contents

Protein chains

219 a.a. *

Ligands

MCO ×4

GOL ×4

Metals

_NA

_ZN ×12

Waters ×720

* Residue conservation analysis

PDB id:

1m2x

Name:

Hydrolase

Title:

Crystal structure of the metallo-beta-lactamase blab of chryseobacterium meningosepticum in complex with the inhibi captopril

Structure:

Class b carbapenemase blab-1. Chain: a, b, c, d. Synonym: metallo-beta-lactamase blab. Engineered: yes

Source:

Elizabethkingia meningoseptica. Organism_taxid: 238. Gene: blab. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.50Å R-factor: 0.190 R-free: 0.208

Authors:

I.Garcia-Saez,O.Dideberg

Key ref:

I.García-Saez et al. (2003). The 1.5-A structure of Chryseobacterium meningosepticum zinc beta-lactamase in complex with the inhibitor, D-captopril. J Biol Chem, 278, 23868-23873. PubMed id: 12684522 DOI: 10.1074/jbc.M301062200

Date:

26-Jun-02 Release date: 29-Jul-03

Protein chains

O08498  (BLAB1_FLAME) -  Carbapenem-hydrolyzing beta-lactamase BlaB-1

Seq: 249 a.a.

Struc: 219 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 

• Biological process: response to antibiotic (2 terms)
• Biochemical function: hydrolase activity (4 terms)

DOI no: 10.1074/jbc.M301062200

J Biol Chem 278:23868-23873 (2003)

PubMed id: 12684522

The 1.5-A structure of Chryseobacterium meningosepticum zinc beta-lactamase in complex with the inhibitor, D-captopril.

I.García-Saez, J.Hopkins, C.Papamicael, N.Franceschini, G.Amicosante, G.M.Rossolini, M.Galleni, J.M.Frère, O.Dideberg.

ABSTRACT

The crystal structure of the class-B beta-lactamase, BlaB, from the pathogenic bacterium, Chryseobacterium meningosepticum, in complex with the inhibitor, d-captopril, has been solved at 1.5-A resolution. The enzyme has the typical alphabeta/betaalpha metallo-beta-lactamase fold and the characteristic two metal binding sites of members of the subclass B1, in which two Zn2+ ions were identified. d-Captopril, a diastereoisomer of the commercial drug, captopril, acts as an inhibitor by displacing the catalytic hydroxyl ion required for antibiotic hydrolysis and intercalating its sulfhydryl group between the two Zn2+ ions. Interestingly, d-captopril is located on one side of the active site cleft. The x-ray structure of the complex of the closely related enzyme, IMP-1, with a mercaptocarboxylate inhibitor, which also contains a sulfhydryl group bound to the two Zn2+ ions, shows the ligand to be located on the opposite side of the active site cleft. A molecule generated by fusion of these two inhibitors would cover the entire cleft, suggesting an interesting approach to the design of highly specific inhibitors.

Selected figure(s)

Figure 2.
FIG. 2. Coordination of D-captopril by BlaB. a, stereoview of the active site of BlaB in complex with D-captopril. The calculated F[o] - F[c] map at 1.5 shows the presence of the inhibitor. The inhibitor atoms were not included in the phase calculation. The residues labeled in black belong to the His site, and those in red belong to the Cys site. Zinc ions are represented as brown spheres. The figure was produced using BOBSCRIPT (54). b, protein-ligand interactions between BlaB and D-captopril depicted in monomer A using LIGPLOT (55). In the schematic drawing, strong interactions are shown as dashed green lines. Ligand and protein hydrophobic contacts are represented as curved red combs. c, active site cleft of BlaB. Zinc ions and water molecules are represented in brown and red spheres, respectively. D-Captopril is displayed in sticks (carbon, nitrogen, and sulfur atoms colored in violet, blue, and green, respectively). Amino acid residues cited in the text under "Structural Comparisons" are labeled, and Zn2^+ ligands are colored in gray.

Figure 3.
FIG. 3. Two inhibitors in the active site cleft. a, GRASP representation (52) of BlaB complexed with both D-captopril (carbons colored in sky blue) and the mercaptocarboxylate inhibitor (carbons colored in orange) from the IMP-1 complex (30) after structural superposition of the BlaB and IMP-1 structures. Both molecules intercalate their sulfur atoms between the two zinc atoms of the active site but are localized in different areas of the active site cavity. b, close-up view of the two inhibitors showing strong interactions between the two inhibitors and BlaB.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 23868-23873) copyright 2003.

Figures were selected by an automated process.