7TI0 | pdb_00007ti0

Structure of CTX-M-15 bound to RPX-7063 at 1.5A

PDB DOI: https://doi.org/10.2210/pdb7TI0/pdb

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

Deposited: 2022-01-12 Released: 2022-05-18
Deposition Author(s): Clifton, M.C., Abendroth, J., Hecker, S.J., Edwards, T.E.
Funding Organization(s): Other private

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.50 Å
R-Value Free:
0.178 (Depositor), 0.190 (DCC)
R-Value Work:
0.160 (Depositor), 0.170 (DCC)
R-Value Observed:
0.160 (Depositor)

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

Broad-spectrum cyclic boronate beta-lactamase inhibitors featuring an intramolecular prodrug for oral bioavailability.

Reddy, K.R., Totrov, M., Lomovskaya, O., Griffith, D.C., Tarazi, Z., Clifton, M.C., Hecker, S.J.

(2022) Bioorg Med Chem 62: 116722-116722

PubMed: 35358864 Search on PubMed
DOI: https://doi.org/10.1016/j.bmc.2022.116722
Primary Citation of Related Structures:
7TI0, 7TI1, 7TI2

PubMed Abstract:
Early efforts to broaden the spectrum and potency of cyclic boronic acid β-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important β-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).

Organizational Affiliation

Qpex Biopharma, Inc, 6275 Nancy Ridge Dr., Suite 100, San Diego, CA 92121, United States.

Macromolecule Content

Total Structure Weight: 28.74 kDa
Atom Count: 2,265
Modelled Residue Count: 260
Deposited Residue Count: 263
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Beta-lactamase	A	263	Klebsiella pneumoniae	Mutation(s): 0 Gene Names: blaCTX-M-15, bla_1, bla_10, bla_2, bla_3, blaCTX-M, CTX-M, CTX-M-15 EC: 3.5.2.6
UniProt
Find proteins for Q2PUH3 (Klebsiella pneumoniae) Explore Q2PUH3 Go to UniProtKB: Q2PUH3
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q2PUH3
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
ZXQ (Subject of Investigation/LOI) Query on ZXQ Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	{(3R,7S)-2-hydroxy-3-[2-(thiophen-2-yl)acetamido]-2,3,4,7-tetrahydro-1,2-oxaborepin-7-yl}acetic acid C₁₃ H₁₆ B N O₅ S JQVILEFLUQMOSI-KOLCDFICSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A]	C [auth A], D [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain C [auth A] Focus chain D [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]