7KH7

Crystal structure of Staphylococcus aureus ketol-acid reductoisomerase in complex with Mg2+, NADPH, and NSC116565

PDB DOI: https://doi.org/10.2210/pdb7KH7/pdb

Classification: ISOMERASE/Inhibitor
Organism(s): Staphylococcus aureus
Expression System: Escherichia coli BL21
Mutation(s): No

Deposited: 2020-10-20 Released: 2021-07-14
Deposition Author(s): Kurz, J.L., Patel, K.P., Guddat, L.W.
Funding Organization(s): National Health and Medical Research Council (NHMRC, Australia)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.63 ?
R-Value Free: 0.303
R-Value Work: 0.246
R-Value Observed: 0.252

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Discovery of a Pyrimidinedione Derivative with Potent Inhibitory Activity against Mycobacterium tuberculosis Ketol-Acid Reductoisomerase.

Lin, X., Kurz, J.L., Patel, K.M., Wun, S.J., Hussein, W.M., Lonhienne, T., West, N.P., McGeary, R.P., Schenk, G., Guddat, L.W.

(2021) Chemistry 27: 3130-3141

PubMed: 33215746 Search on PubMed
DOI: https://doi.org/10.1002/chem.202004665
Primary Citation of Related Structures:
7KE2, 7KH7

PubMed Abstract:
New drugs aimed at novel targets are urgently needed to combat the increasing rate of drug-resistant tuberculosis (TB). Herein, the National Cancer Institute Developmental Therapeutic Program (NCI-DTP) chemical library was screened against a promising new target, ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway. From this library, 6-hydroxy-2-methylthiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (NSC116565) was identified as a potent time-dependent inhibitor of Mycobacterium?tuberculosis (Mt) KARI with a K _i of 95.4?nm. Isothermal titration calorimetry studies showed that this inhibitor bound to MtKARI in the presence and absence of the cofactor, nicotinamide adenine dinucleotide phosphate (NADPH), which was confirmed by crystal structures of the compound in complex with closely related Staphylococcus?aureus KARI. It is also shown that NSC116565 inhibits the growth of H37Ra and H37Rv strains of Mt with MIC ₅₀ values of 2.93 and 6.06?μm, respectively. These results further validate KARI as a TB drug target and show that NSC116565 is a promising lead for anti-TB drug development.

Organizational Affiliation

School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia.

Macromolecule Content

Total Structure Weight: 77.78 kDa
Atom Count: 5,158
Modelled Residue Count: 642
Deposited Residue Count: 680
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Ketol-acid reductoisomerase (NADP(+))	A, B	340	Staphylococcus aureus	Mutation(s): 0 Gene Names: ilvC, BMF23_13825, BO217_1422, ERS072840_02559 EC: 1.1.1.86
UniProt
Find proteins for Q2FWK4 (Staphylococcus aureus (strain NCTC 8325 / PS 47)) Explore Q2FWK4 Go to UniProtKB: Q2FWK4
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q2FWK4
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NDP Query on NDP Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₃₀ N₇ O₁₇ P₃ ACFIXJIJDZMPPO-NNYOXOHSSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
NAP Query on NAP Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₂₈ N₇ O₁₇ P₃ XJLXINKUBYWONI-NNYOXOHSSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
WBY (Subject of Investigation/LOI) Query on WBY Download Ideal Coordinates CCD File SDF format, chain H [auth B] SDF format, chain I [auth B] MOL2 format, chain H [auth B] MOL2 format, chain I [auth B] mmCIF format, chain H [auth B] mmCIF format, chain I [auth B]	H [auth B], I [auth B]	6-hydroxy-2-methyl[1,3]thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione C₆ H₅ N₃ O₃ S MYPICMPDMGFOBX-UHFFFAOYSA-N		Interactions Focus chain H [auth B] Focus chain I [auth B] Interactions & Density Focus chain H [auth B] Focus chain I [auth B]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain K [auth B] SDF format, chain J [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain K [auth B] MOL2 format, chain J [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain K [auth B] mmCIF format, chain J [auth B]	E [auth A], F [auth A], G [auth A], J [auth B], K [auth B]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B] Focus chain K [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B] Focus chain K [auth B]