PDBsum entry 5o2f

Hydrolase

PDB id: 5o2f

Contents

Protein chains

243 a.a.

Ligands

ZZ7 ×2

SO4 ×4

EDO ×3

Metals

_ZN ×4

_CL

Waters ×433

PDB id:

5o2f

Name:

Hydrolase

Title:

Crystal structure of ndm-1 in complex with hydrolyzed ampicillin - new refinement

Structure:

Metallo-beta-lactamase type 2. Chain: a, b. Synonym: b2 metallo-beta-lactamase,beta-lactamase type ii,metallo- beta-lactamase ndm-1,metallo-beta-lactamase type ii,new delhi metallo-beta-lactamase-1,ndm-1. Engineered: yes

Source:

Klebsiella pneumoniae. Organism_taxid: 573. Gene: blandm-1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.01Å R-factor: 0.135 R-free: 0.182

Authors:

J.E.Raczynska,I.G.Shabalin,M.Jaskolski,W.Minor,A.Wlodawer

Key ref:

J.E.Raczynska et al. (2018). A close look onto structural models and primary ligands of metallo-β-lactamases. Drug Resist Updat, 40, 1. PubMed id: 30466711

Date:

20-May-17 Release date: 26-Dec-18

Protein chains

C7C422  (BLAN1_KLEPN) -  Metallo-beta-lactamase type 2 from Klebsiella pneumoniae

Seq: 270 a.a.

Struc: 243 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+)

Drug Resist Updat 40:1 (2018)

PubMed id: 30466711

A close look onto structural models and primary ligands of metallo-β-lactamases.

J.E.Raczynska, I.G.Shabalin, W.Minor, A.Wlodawer, M.Jaskolski.

ABSTRACT

β-Lactamases are hydrolytic enzymes capable of opening the β-lactam ring of antibiotics such as penicillin, thus endowing the bacteria that produce them with antibiotic resistance. Of particular medical concern are metallo-β-lactamases (MBLs), with an active site built around coordinated Zn cations. MBLs are pan-reactive enzymes that can break down almost all classes of β-lactams, including such last-resort antibiotics as carbapenems. They are not only broad-spectrum-reactive but are often plasmid-borne (e.g., the New Delhi enzyme, NDM), and can spread horizontally even among unrelated bacteria. Acquired MBLs are encoded by mobile genetic elements, which often include other resistance genes, making the microbiological situation particularly alarming. There is an urgent need to develop MBL inhibitors in order to rescue our antibiotic armory. A number of such efforts have been undertaken, most notably using the 3D structures of various MBLs as drug-design targets. Structure-guided drug discovery depends on the quality of the structures that are collected in the Protein Data Bank (PDB) and on the consistency of the information in dedicated β-lactamase databases. We conducted a careful review of the crystal structures of class B β-lactamases, concluding that the quality of these structures varies widely, especially in the regions where small molecules interact with the macromolecules. In a number of examples the interpretation of the bound ligands (e.g., inhibitors, substrate/product analogs) is doubtful or even incorrect, and it appears that in some cases the modeling of ligands was not supported by electron density. For ten MBL structures, alternative interpretations of the original diffraction data could be proposed and the new models have been deposited in the PDB. In four cases, these models, prepared jointly with the authors of the original depositions, superseded the previous deposits. This review emphasizes the importance of critical assessment of structural models describing key drug design targets at the level of the raw experimental data. Since the structures reviewed here are the basis for ongoing design of new MBL inhibitors, it is important to identify and correct the problems with ambiguous crystallographic interpretations, thus enhancing reproducibility in this highly medically relevant area.