6B1W | pdb_00006b1w

Crystal structure KPC-2 beta-lactamase complexed with WCK 5107 by co-crystallization

PDB DOI: https://doi.org/10.2210/pdb6B1W/pdb

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

Deposited: 2017-09-19 Released: 2018-08-01
Deposition Author(s): van den Akker, F., Nguyen, N.Q.
Funding Organization(s): Wockhardt

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.73 Å
R-Value Free:
0.194 (Depositor), 0.200 (DCC)
R-Value Work:
0.152 (Depositor), 0.160 (DCC)
R-Value Observed:
0.154 (Depositor)

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using beta-Lactamase Inhibitors and beta-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234.

Papp-Wallace, K.M., Nguyen, N.Q., Jacobs, M.R., Bethel, C.R., Barnes, M.D., Kumar, V., Bajaksouzian, S., Rudin, S.D., Rather, P.N., Bhavsar, S., Ravikumar, T., Deshpande, P.K., Patil, V., Yeole, R., Bhagwat, S.S., Patel, M.V., van den Akker, F., Bonomo, R.A.

(2018) J Med Chem 61: 4067-4086

PubMed: 29627985 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.8b00091
Primary Citation of Related Structures:
6B1F, 6B1H, 6B1J, 6B1W, 6B1X, 6B1Y, 6B22

PubMed Abstract:
Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum β-lactamases. The design of novel β-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C, and D β-lactamases with unprecedented k ₂/ K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C β-lactamses rapidly but not the tested OXAs. Compounds 1-3 formed highly stable acyl-complexes as demonstrated by mass spectrometry. Crystallography revealed that 1-3 complexed with KPC-2 adopted a "chair conformation" with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were effective in murine peritonitis and neutropenic lung infection models caused by MDR Acinetobacter baumannii. Compounds 1-3 are novel β-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted.

Organizational Affiliation

Research Service , Louis Stokes Cleveland Department of Veterans Affairs Medical Center , 10701 East Boulevard , Cleveland , Ohio 44106 , United States.

Macromolecule Content

Total Structure Weight: 58.13 kDa
Atom Count: 4,462
Modelled Residue Count: 533
Deposited Residue Count: 536
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Carbapenem-hydrolyzing beta-lactamase KPC	A, B	268	Klebsiella pneumoniae	Mutation(s): 0 Gene Names: bla, kpc, kpc1 EC: 3.5.2.6
UniProt
Find proteins for Q9F663 (Klebsiella pneumoniae) Explore Q9F663 Go to UniProtKB: Q9F663
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9F663
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
C8V (Subject of Investigation/LOI) Query on C8V Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain L [auth B] MOL2 format, chain F [auth A] MOL2 format, chain L [auth B] mmCIF format, chain F [auth A] mmCIF format, chain L [auth B]	F [auth A], L [auth B]	(2S,5R)-1-formyl-N'-[(3R)-piperidine-3-carbonyl]-5-[(sulfooxy)amino]piperidine-2-carbohydrazide C₁₃ H₂₃ N₅ O₇ S KMYLRFCWFBWPGR-MXWKQRLJSA-N		Interactions Focus chain F [auth A] Focus chain L [auth B] Interactions & Density Focus chain F [auth A] Focus chain L [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain G [auth B] SDF format, chain H [auth B] SDF format, chain I [auth B] SDF format, chain J [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain G [auth B] MOL2 format, chain H [auth B] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain G [auth B] mmCIF format, chain H [auth B] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B]	C [auth A] D [auth A] G [auth B] H [auth B] I [auth B] C [auth A], D [auth A], G [auth B], H [auth B], I [auth B], J [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain G [auth B] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain G [auth B] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain K [auth B] MOL2 format, chain E [auth A] MOL2 format, chain K [auth B] mmCIF format, chain E [auth A] mmCIF format, chain K [auth B]	E [auth A], K [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain E [auth A] Focus chain K [auth B] Interactions & Density Focus chain E [auth A] Focus chain K [auth B]