PDBsum entry 7mcp

Lyase

PDB id: 7mcp

Contents

Protein chains

380 a.a.

Ligands

PLP ×2

GOL ×4

Metals

_NA ×6

Waters ×496

PDB id:

7mcp

Name:

Lyase

Title:

Crystal structure of staphylococcus aureus cystathionine gamma-lyase, holoenzyme dimer

Structure:

Bifunctional cystathionine gamma-lyase/homocysteine desulfhydrase. Chain: a, h. Synonym: cystathionine beta-lyase,cystathionine gamma-lyase, cystathionine gamma-synthase. Engineered: yes

Source:

Staphylococcus aureus. Organism_taxid: 1280. Gene: mccb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

2.40Å R-factor: 0.150 R-free: 0.173

Authors:

A.Nuthanakanti,A.Serganov,A.Kaushik

Key ref:

K.Shatalin et al. (2021). Inhibitors of bacterial H₂S biogenesis targeting antibiotic resistance and tolerance. Science, 372, 1169-1175. PubMed id: 34112687

Date:

02-Apr-21 Release date: 23-Jun-21

Protein chains

A0A0H3K724  (A0A0H3K724_STAAE) -  Cystathionine gamma-synthase from Staphylococcus aureus (strain Newman)

Seq: 380 a.a.

Struc: 380 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.5.1.48 - cystathionine gamma-synthase.
• Reaction: O-succinyl-L-homoserine + L-cysteine = L,L-cystathionine + succinate + H⁺

O-succinyl-L-homoserine (Bound ligand (Het Group name = GOL) matches with 44.44% similarity) + L-cysteine = L,L-cystathionine + succinate + H(+)

• Cofactor: Pyridoxal 5'-phosphate

Pyridoxal 5'-phosphate (Bound ligand (Het Group name = PLP) matches with 93.75% similarity)

• Enzyme class 2: E.C.4.4.1.1 - cystathionine gamma-lyase.
• Reaction: L,L-cystathionine + H2O = 2-oxobutanoate + L-cysteine + NH4⁺
• Cofactor: Pyridoxal 5'-phosphate
• Enzyme class 3: E.C.4.4.1.8 - Transferred entry: 4.4.1.13.
• Reaction: L-cystathionine + H₂O = L-homocysteine + NH₃ + pyruvate
• Cofactor: Pyridoxal 5'-phosphate

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Science 372:1169-1175 (2021)

PubMed id: 34112687

Inhibitors of bacterial H₂S biogenesis targeting antibiotic resistance and tolerance.

K.Shatalin, A.Nuthanakanti, A.Kaushik, D.Shishov, A.Peselis, I.Shamovsky, B.Pani, M.Lechpammer, N.Vasilyev, E.Shatalina, D.Rebatchouk, A.Mironov, P.Fedichev, A.Serganov, E.Nudler.

ABSTRACT

Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H₂S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H₂S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H₂S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.