PDBsum entry 5dts

Hydrolase

PDB id: 5dts

Contents

Protein chains

241 a.a.

Ligands

5F8 ×4

Metals

_CL ×2

Waters ×908

PDB id:

5dts

Name:

Hydrolase

Title:

Fragments bound to the oxa-48 beta-lactamase: compound 2

Structure:

Beta-lactamase. Chain: a, b, c, d. Engineered: yes

Source:

Klebsiella pneumoniae. Organism_taxid: 573. Gene: bla oxa-48, blaoxa-48, kpe71t_00045. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.94Å R-factor: 0.240 R-free: 0.274

Authors:

B.A.Lund,T.Christopeit,H.-K.S.Leiros

Key ref:

B.A.Lund et al. (2016). Screening and Design of Inhibitor Scaffolds for the Antibiotic Resistance Oxacillinase-48 (OXA-48) through Surface Plasmon Resonance Screening. J Med Chem, 59, 5542-5554. PubMed id: 27165692 DOI: 10.1021/acs.jmedchem.6b00660

Date:

18-Sep-15 Release date: 25-May-16

Protein chains

Q6XEC0  (Q6XEC0_KLEPN) -  Beta-lactamase from Klebsiella pneumoniae

Seq: 265 a.a.

Struc: 241 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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/acs.jmedchem.6b00660

J Med Chem 59:5542-5554 (2016)

PubMed id: 27165692

Screening and Design of Inhibitor Scaffolds for the Antibiotic Resistance Oxacillinase-48 (OXA-48) through Surface Plasmon Resonance Screening.

B.A.Lund, T.Christopeit, Y.Guttormsen, A.Bayer, H.K.Leiros.

ABSTRACT

The spread of antibiotic resistant bacteria is a global threat that shakes the foundations of modern healthcare. β-Lactamases are enzymes that confer resistance to β-lactam antibiotics in bacteria, and there is a critical need for new inhibitors of these enzymes for combination therapy together with an antibiotic. With this in mind, we have screened a library of 490 fragments to identify starting points for the development of new inhibitors of the class D β-lactamase oxacillinase-48 (OXA-48) through surface plasmon resonance (SPR), dose-rate inhibition assays, and X-ray crystallography. Furthermore, we have uncovered structure-activity relationships and used alternate conformations from a crystallographic structure to grow a fragment into a more potent compound with a KD of 50 μM and an IC50 of 18 μM.