3CG5

Crystal Structure of the Covalent Adduct Formed between TB B-lactamase and Clavulanate

Summary for 3CG5

• Entry DOI: 10.2210/pdb3cg5/pdb
• Descriptor: Beta-lactamase, PHOSPHATE ION, (2E)-3-[(4-hydroxy-2-oxobutyl)amino]prop-2-enal, ... (4 entities in total)
• Functional Keywords: alpha-beta structure, covalent adduct, antibiotic resistance, hydrolase, lipoprotein, membrane, palmitate
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cell membrane; Lipid-anchor (Potential): P0C5C1
• Total number of polymer chains: 1
• Total formula weight: 28809.77

Authors

Tremblay, L.W.,Hugonnet, J.E.,Blanchard, J.S. (deposition date: 2008-03-04, release date: 2008-05-27, Last modification date: 2024-11-06)

Primary citation

Tremblay, L.W.,Hugonnet, J.E.,Blanchard, J.S.
Structure of the covalent adduct formed between Mycobacterium tuberculosis beta-lactamase and clavulanate.
Biochemistry, 47:5312-5316, 2008

PubMed Abstract: The intrinsic resistance of Mycobacterium tuberculosis to the beta-lactam class of antibiotics arises from a chromosomally encoded, extended spectrum, class A beta-lactamase, BlaC. Herein, we report the X-ray crystallographic structure of BlaC inhibited with clavulanate at a resolution of 1.7 A with an R-factor value of 0.180 and R-free value of 0.212 for the m/ z +154 clavulanate-derived fragment observed in the active site. Structural evidence reveals the presence of hydrogen bonds to the C1 carbonyl along with a coplanar arrangement of C1, C2, C3, and N4, which favors enolization to generate a trans-alpha,beta-eneamine, stabilizing the +154 adduct from hydrolysis. The irreversible inhibition of BlaC suggests that treatment of M. tuberculosis with a combination of a beta-lactam antibiotic and clavulanate may lead to rapid bactericidal activity.

PubMed: 18422342
DOI: 10.1021/bi8001055

Experimental method

X-RAY DIFFRACTION (1.7 Å)