7CET

Crystal structure of D-cycloserine-bound form of cysteine desulfurase NifS from Helicobacter pylori

PDB DOI: https://doi.org/10.2210/pdb7CET/pdb

Classification: BIOSYNTHETIC PROTEIN
Organism(s): Helicobacter pylori 26695
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2020-06-24 Released: 2021-06-30
Deposition Author(s): Nakamura, R., Takahashi, Y., Fujishiro, T.
Funding Organization(s): Japan Society for the Promotion of Science (JSPS)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.64 Å
R-Value Free: 0.242
R-Value Work: 0.194
R-Value Observed: 0.197

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

Cycloserine enantiomers inhibit PLP-dependent cysteine desulfurase SufS via distinct mechanisms.

Nakamura, R., Ogawa, S., Takahashi, Y., Fujishiro, T.

(2022) FEBS J

PubMed: 35395703 Search on PubMed
DOI: https://doi.org/10.1111/febs.16455
Primary Citation of Related Structures:
6KFY, 7CEO, 7CEP, 7CEQ, 7CER, 7CES, 7CET, 7CEU, 7E6A, 7E6B, 7E6C, 7E6D, 7E6E, 7E6F

PubMed Abstract:
The cysteine desulfurase SufS is a pyridoxal-5'-phosphate-dependent enzyme and is essential for the SUF system, which participates in iron-sulfur cluster biosynthesis. Inhibition of SufS in the SUF system by D-cycloserine (DCS) in Plasmodium falciparum apicoplast has recently been reported, indicating that SufS could be a target for malaria therapeutics. However, the mechanistic details underlying the inhibition of SufS by DCS have not yet been clarified. Moreover, inhibition of SufS by the other enantiomer, L-cycloserine (LCS), has not been investigated. Herein, we investigated the structure-based inhibition mechanisms of SufS by DCS and LCS using Bacillus subtilis SufS, whose catalytic mechanism has been well characterized in comparison to that of the P. falciparum SufS. Surprisingly, DCS- and LCS-mediated inhibitions of SufS occur via distinct mechanisms resulting in pyridoxamine-5'-phosphate (PMP) in DCS-mediated inhibition and PMP-3-hydroxyisoxazole adduct (PMP-isoxazole) in LCS-mediated inhibition. Biochemical and structural evaluation of SufS variants identified conserved His and Arg residues at the active site as the key determinants of the distinct inhibition mechanisms. The importance of structural elements involved in DCS and LCS-mediated inhibitions of SufS provides valuable insights for the structure-based design of new drugs targeting SufS. DATABASE: Structural data are available in PDB database under the accession numbers 6KFY, 7CEO, 7CEP, 7CEQ, 7CER, 7CES, 7CET, 7CEU, 7E6A, 7E6B, 7E6C, 7E6D, 7E6E, and 7E6F.

Organizational Affiliation

Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, Japan.

Macromolecule Content

Total Structure Weight: 44.55 kDa
Atom Count: 2,852
Modelled Residue Count: 359
Deposited Residue Count: 401
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Cysteine desulfurase IscS	A	401	Helicobacter pylori 26695	Mutation(s): 2 Gene Names: iscS, HP_0220 EC: 2.8.1.7
UniProt
Find proteins for O25008 (Helicobacter pylori (strain ATCC 700392 / 26695)) Explore O25008 Go to UniProtKB: O25008
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O25008
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
7TS (Subject of Investigation/LOI) Query on 7TS 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]	(5-hydroxy-6-methyl-4-{[(3-oxo-2,3-dihydro-1,2-oxazol-4-yl)amino]methyl}pyridin-3-yl)methyl dihydrogen phosphate C₁₁ H₁₄ N₃ O₇ P PXWFNGNWQUPGPJ-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
IPA Query on IPA 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]	ISOPROPYL ALCOHOL C₃ H₈ O KFZMGEQAYNKOFK-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
CL Query on CL 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]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]