5A5Z

Approved Drugs Containing Thiols as Inhibitors of Metallo-beta- lactamases: Strategy To Combat Multidrug-Resistant Bacteria

PDB DOI: https://doi.org/10.2210/pdb5A5Z/pdb

Classification: HYDROLASE
Organism(s): Klebsiella pneumoniae
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2015-06-23 Released: 2015-07-08
Deposition Author(s): Klingler, F.M., Wichelhaus, T.A., Frank, D., Cuesta-Bernal, J., El-Delik, J., Mueller, H.F., Sjuts, H., Goettig, S., Koenigs, A., Pogoryelov, D., Proschak, E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.60 ?
R-Value Free: 0.252
R-Value Work: 0.208
R-Value Observed: 0.210

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Re-refinement Note

A newer entry is available that reflects an alternative modeling of the original data: 5NBK

Literature

Approved Drugs Containing Thiols as Inhibitors of Metallo-beta-lactamases: Strategy To Combat Multidrug-Resistant Bacteria.

Klingler, F.M., Wichelhaus, T.A., Frank, D., Cuesta-Bernal, J., El-Delik, J., Muller, H.F., Sjuts, H., Gottig, S., Koenigs, A., Pos, K.M., Pogoryelov, D., Proschak, E.

(2015) J Med Chem 58: 3626-3630

PubMed: 25815530 Search on PubMed
DOI: https://doi.org/10.1021/jm501844d
Primary Citation of Related Structures:
5A5Z

PubMed Abstract:
Resistance to β-lactam antibiotics can be mediated by metallo-β-lactamase enzymes (MBLs). An MBL inhibitor could restore the effectiveness of β-lactams. We report on the evaluation of approved thiol-containing drugs as inhibitors of NDM-1, VIM-1, and IMP-7. Drugs were assessed by a novel assay using a purchasable fluorescent substrate and thermal shift. Best compounds were tested in antimicrobial susceptibility assay. Using these orthogonal screening methods, we identified drugs that restored the activity of imipenem.

Organizational Affiliation

§Institute of Medical Microbiology and Infection Control, Paul-Ehrlich-Stra?e 40, 60596 Frankfurt, Germany.

Macromolecule Content

Total Structure Weight: 54.26 kDa
Atom Count: 3,614
Modelled Residue Count: 472
Deposited Residue Count: 502
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
BETA-LACTAMASE NDM-1	A, B [auth C]	251	Klebsiella pneumoniae	Mutation(s): 0 EC: 3.5.2.6
UniProt
Find proteins for C7C422 (Klebsiella pneumoniae) Explore C7C422 Go to UniProtKB: C7C422
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	C7C422
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
WJZ Query on WJZ Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth C] MOL2 format, chain E [auth A] MOL2 format, chain H [auth C] mmCIF format, chain E [auth A] mmCIF format, chain H [auth C]	E [auth A], H [auth C]	TIOPRONIN C₅ H₉ N O₃ S YTGJWQPHMWSCST-VKHMYHEASA-N		Interactions Focus chain E [auth A] Focus chain H [auth C] Interactions & Density Focus chain E [auth A] Focus chain H [auth C]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain F [auth C] SDF format, chain G [auth C] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain F [auth C] MOL2 format, chain G [auth C] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain F [auth C] mmCIF format, chain G [auth C]	C [auth A], D [auth A], F [auth C], G [auth C]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain F [auth C] Focus chain G [auth C] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain F [auth C] Focus chain G [auth C]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.60 ?
R-Value Free: 0.252
R-Value Work: 0.208
R-Value Observed: 0.210
Space Group: P 4₁ 2₁ 2

Unit Cell:

Length ( ? )	Angle ( ? )
a = 108.047	α = 90
b = 108.047	β = 90
c = 92.571	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data reduction
XSCALE	data scaling
PHENIX	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2015-07-08

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2015-07-08
Type: Initial release
Version 1.1: 2019-02-27
Changes: Data collection, Database references, Experimental preparation, Other
Version 1.2: 2024-01-10
Changes: Data collection, Database references, Derived calculations, Other, Refinement description