5DTK

Fragments bound to the OXA-48 beta-lactamase: Compound 17

PDB DOI: https://doi.org/10.2210/pdb5DTK/pdb

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

Deposited: 2015-09-18 Released: 2016-05-25
Deposition Author(s): Lund, B.A., Christopeit, T., Leiros, H.-K.S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.60 ?
R-Value Free: 0.172
R-Value Work: 0.146
R-Value Observed: 0.146

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.

Literature

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

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

(2016) J Med Chem 59: 5542-5554

PubMed: 27165692 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.6b00660
Primary Citation of Related Structures:
5DTK, 5DTS, 5DTT, 5DVA

PubMed 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.

Organizational Affiliation

The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, UiT The Arctic University of Norway , 9037 Troms?, Norway.

Macromolecule Content

Total Structure Weight: 123.74 kDa
Atom Count: 9,524
Modelled Residue Count: 972
Deposited Residue Count: 1,060
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	A, B, C, D	265	Klebsiella pneumoniae	Mutation(s): 0 Gene Names: bla OXA-48, blaOXA-48, KPE71T_00045 EC: 3.5.2.6
UniProt
Find proteins for Q6XEC0 (Klebsiella pneumoniae) Explore Q6XEC0 Go to UniProtKB: Q6XEC0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q6XEC0
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
5F3 Query on 5F3 Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain K [auth B] SDF format, chain U [auth C] SDF format, chain V [auth D] MOL2 format, chain J [auth A] MOL2 format, chain K [auth B] MOL2 format, chain U [auth C] MOL2 format, chain V [auth D] mmCIF format, chain J [auth A] mmCIF format, chain K [auth B] mmCIF format, chain U [auth C] mmCIF format, chain V [auth D]	J [auth A], K [auth B], U [auth C], V [auth D]	3,5-di(pyridin-4-yl)benzoic acid C₁₇ H₁₂ N₂ O₂ NNTKTJCJOPINGZ-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain K [auth B] Focus chain U [auth C] Focus chain V [auth D] Interactions & Density Focus chain J [auth A] Focus chain K [auth B] Focus chain U [auth C] Focus chain V [auth D]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain P [auth C] SDF format, chain Q [auth C] SDF format, chain R [auth C] SDF format, chain S [auth C] SDF format, chain T [auth C] SDF format, chain W [auth D] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain P [auth C] MOL2 format, chain Q [auth C] MOL2 format, chain R [auth C] MOL2 format, chain S [auth C] MOL2 format, chain T [auth C] MOL2 format, chain W [auth D] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain P [auth C] mmCIF format, chain Q [auth C] mmCIF format, chain R [auth C] mmCIF format, chain S [auth C] mmCIF format, chain T [auth C] mmCIF format, chain W [auth D]	F [auth A] G [auth A] H [auth A] I [auth A] L [auth B] F [auth A], G [auth A], H [auth A], I [auth A], L [auth B], M [auth B], N [auth B], P [auth C], Q [auth C], R [auth C], S [auth C], T [auth C], W [auth D]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Focus chain P [auth C] Focus chain Q [auth C] Focus chain R [auth C] Focus chain S [auth C] Focus chain T [auth C] Focus chain W [auth D] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Focus chain P [auth C] Focus chain Q [auth C] Focus chain R [auth C] Focus chain S [auth C] Focus chain T [auth C] Focus chain W [auth D]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain O [auth C] MOL2 format, chain E [auth A] MOL2 format, chain O [auth C] mmCIF format, chain E [auth A] mmCIF format, chain O [auth C]	E [auth A], O [auth C]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain E [auth A] Focus chain O [auth C] Interactions & Density Focus chain E [auth A] Focus chain O [auth C]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
KCX Query on KCX	A, B, C, D	L-PEPTIDE LINKING	C₇ H₁₄ N₂ O₄		LYS

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.60 ?
R-Value Free: 0.172
R-Value Work: 0.146
R-Value Observed: 0.146
Space Group: P 1 2₁ 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 45.523	α = 90
b = 124.31	β = 98.263
c = 108.742	γ = 90

Software Package:

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

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2016-05-25

Deposition Author(s):

Lund, B.A.

Christopeit, T.

Leiros, H.-K.S.

Revision History (Full details and data files)

Version 1.0: 2016-05-25
Type: Initial release
Version 1.1: 2016-06-22
Changes: Database references
Version 1.2: 2024-01-10
Changes: Data collection, Database references, Refinement description

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Help and Resources

5DTK

Fragments bound to the OXA-48 beta-lactamase: Compound 17

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

Entity ID: 1

UniProt

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)