7E6E

Crystal structure of PMP-bound form of cysteine desulfurase SufS R376A from Bacillus subtilis in D-cycloserine-inhibition

PDB DOI: https://doi.org/10.2210/pdb7E6E/pdb

Classification: BIOSYNTHETIC PROTEIN
Organism(s): Bacillus subtilis subsp. subtilis str. 168
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2021-02-22 Released: 2022-03-02
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: 2.28 ?
R-Value Free: 0.178
R-Value Work: 0.162
R-Value Observed: 0.163

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 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 289: 5947-5970

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: 47.74 kDa
Atom Count: 3,393
Modelled Residue Count: 412
Deposited Residue Count: 419
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 SufS	A	419	Bacillus subtilis subsp. subtilis str. 168	Mutation(s): 1 Gene Names: sufS, csd, yurW, BSU32690 EC: 2.8.1.7
UniProt
Find proteins for O32164 (Bacillus subtilis (strain 168)) Explore O32164 Go to UniProtKB: O32164
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O32164
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
PMP Query on PMP 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]	4'-DEOXY-4'-AMINOPYRIDOXAL-5'-PHOSPHATE C₈ H₁₃ N₂ O₅ P ZMJGSOSNSPKHNH-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
PG4 Query on PG4 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]	TETRAETHYLENE GLYCOL C₈ H₁₈ O₅ UWHCKJMYHZGTIT-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
PEG Query on PEG Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A]	D [auth A], E [auth A], F [auth A], G [auth A]	DI(HYDROXYETHYL)ETHER C₄ H₁₀ O₃ MTHSVFCYNBDYFN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A]	H [auth A] I [auth A] J [auth A] K [auth A] L [auth A] H [auth A], I [auth A], J [auth A], K [auth A], L [auth A], M [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Interactions & Density Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A]