4X6T

M.tuberculosis betalactamase complexed with inhibitor EC19

Summary for 4X6T

• Entry DOI: 10.2210/pdb4x6t/pdb
• Descriptor: Beta-lactamase, PHOSPHATE ION, 3-[(2R)-2-(dihydroxyboranyl)-2-{[(2R)-2-{[(4-ethyl-2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)carbonyl]amino}-2-(4-hydroxyphenyl)acetyl]amino}ethyl]benzoic acid, ... (4 entities in total)
• Functional Keywords: beta-lactamase, transition state inhibitor, structure based drug development, beta-lactams, boronates, penicillin binding protein., hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cell inner membrane : P9WKD3
• Total number of polymer chains: 1
• Total formula weight: 29317.72

Authors

Hazra, S. (deposition date: 2014-12-09, release date: 2015-12-23, Last modification date: 2023-09-27)

Primary citation

Kurz, S.G.,Hazra, S.,Bethel, C.R.,Romagnoli, C.,Caselli, E.,Prati, F.,Blanchard, J.S.,Bonomo, R.A.
Inhibiting the beta-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs).
ACS Infect Dis, 1:234-242, 2015

PubMed Abstract: BlaC, the single chromosomally encoded β-lactamase of Mycobacterium tuberculosis, has been identified as a promising target for novel therapies that rely upon β-lactamase inhibition. Boronic acid transition-state inhibitors (BATSIs) are a class of β-lactamase inhibitors which permit rational inhibitor design by combinations of various R1 and R2 side chains. To explore the structural determinants of effective inhibition, we screened a panel of 25 BATSIs to explore key structure-function relationships. We identified a cefoperazone analogue, EC19, which displayed slow, time-dependent inhibition against BlaC with a potency similar to that of clavulanate (Ki* of 0.65 ± 0.05 μM). To further characterize the molecular basis of inhibition, we solved the crystallographic structure of the EC19-BlaC(N172A) complex and expanded our analysis to variant enzymes. The results of this structure-function analysis encourage the design of a novel class of β-lactamase inhibitors, BATSIs, to be used against Mycobacterium tuberculosis.

PubMed: 27622739
DOI: 10.1021/acsinfecdis.5b00003

Experimental method

X-RAY DIFFRACTION (1.4 Å)