PDBsum entry 4x6t

Hydrolase/hydrolase inhibitor

PDB id: 4x6t

Contents

Protein chain

265 a.a.

Ligands

PO4 ×7

3Y6

Waters ×263

PDB id:

4x6t

Name:

Hydrolase/hydrolase inhibitor

Title:

M.Tuberculosis betalactamase complexed with inhibitor ec19

Structure:

Beta-lactamase. Chain: a. Fragment: unp residues 45-307. Synonym: ambler class a beta-lactamase. Engineered: yes. Mutation: yes

Source:

Mycobacterium tuberculosis. Organism_taxid: 83332. Strain: atcc 25618 / h37rv. Gene: blac, blaa, rv2068c, mtcy49.07c. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.40Å R-factor: 0.168 R-free: 0.202

Authors:

S.Hazra

Key ref:

S.G.Kurz et al. (2015). Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs). ACS Infect Dis, 1, 234-242. PubMed id: 27622739 DOI: 10.1021/acsinfecdis.5b00003

Date:

09-Dec-14 Release date: 23-Dec-15

Protein chain

P9WKD3  (BLAC_MYCTU) -  Beta-lactamase from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 307 a.a.

Struc: 265 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

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: Zn(2+)

DOI no: 10.1021/acsinfecdis.5b00003

ACS Infect Dis 1:234-242 (2015)

PubMed id: 27622739

Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs).

S.G.Kurz, S.Hazra, C.R.Bethel, C.Romagnoli, E.Caselli, F.Prati, J.S.Blanchard, R.A.Bonomo.

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.