Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structural basis of broad-spectrum β-lactam resistance in Staphylococcus aureus.
Journal, issue, pages	Nature, Vol. 613, Issue 7943, Page 375-382, Year 2023
Publish date	Jan 4, 2023
Authors	J Andrew N Alexander / Liam J Worrall / Jinhong Hu / Marija Vuckovic / Nidhi Satishkumar / Raymond Poon / Solmaz Sobhanifar / Federico I Rosell / Joshua Jenkins / Daniel Chiang / Wesley A Mosimann / Henry F Chambers / Mark Paetzel / Som S Chatterjee / Natalie C J Strynadka /
PubMed Abstract	Broad-spectrum β-lactam antibiotic resistance in Staphylococcus aureus is a global healthcare burden. In clinical strains, resistance is largely controlled by BlaR1, a receptor that senses β- ...Broad-spectrum β-lactam antibiotic resistance in Staphylococcus aureus is a global healthcare burden. In clinical strains, resistance is largely controlled by BlaR1, a receptor that senses β-lactams through the acylation of its sensor domain, inducing transmembrane signalling and activation of the cytoplasmic-facing metalloprotease domain. The metalloprotease domain has a role in BlaI derepression, inducing blaZ (β-lactamase PC1) and mecA (β-lactam-resistant cell-wall transpeptidase PBP2a) expression. Here, overcoming hurdles in isolation, we show that BlaR1 cleaves BlaI directly, as necessary for inactivation, with no requirement for additional components as suggested previously. Cryo-electron microscopy structures of BlaR1-the wild type and an autocleavage-deficient F284A mutant, with or without β-lactam-reveal a domain-swapped dimer that we suggest is critical to the stabilization of the signalling loops within. BlaR1 undergoes spontaneous autocleavage in cis between Ser283 and Phe284 and we describe the catalytic mechanism and specificity underlying the self and BlaI cleavage. The structures suggest that allosteric signalling emanates from β-lactam-induced exclusion of the prominent extracellular loop bound competitively in the sensor-domain active site, driving subsequent dynamic motions, including a shift in the sensor towards the membrane and accompanying changes in the zinc metalloprotease domain. We propose that this enhances the expulsion of autocleaved products from the active site, shifting the equilibrium to a state that is permissive of efficient BlaI cleavage. Collectively, this study provides a structure of a two-component signalling receptor that mediates action-in this case, antibiotic resistance-through the direct cleavage of a repressor.
External links	Nature / PubMed:36599987 / PubMed Central
Methods	EM (single particle)
Resolution	3.8 - 4.9 Å
Structure data	28658 8exp EMDB-28658, PDB-8exp: Cryo-EM structure of S. aureus BlaR1 with C2 symmetry Method: EM (single particle) / Resolution: 4.2 Å 28659 8exq EMDB-28659, PDB-8exq: Cryo-EM structure of S. aureus BlaR1 with C1 symmetry Method: EM (single particle) / Resolution: 4.9 Å 28660 8exr EMDB-28660, PDB-8exr: Cryo-EM structure of S. aureus BlaR1 TM and zinc metalloprotease domain Method: EM (single particle) / Resolution: 3.8 Å 28661 8exs EMDB-28661, PDB-8exs: Cryo-EM structure of S. aureus BlaR1 F284A mutant Method: EM (single particle) / Resolution: 4.3 Å 28662 8ext EMDB-28662, PDB-8ext: Cryo-EM structure of S. aureus BlaR1 F284A mutant in complex with ampicillin Method: EM (single particle) / Resolution: 4.6 Å
Chemicals	ChemComp-ZN: Unknown entry ChemComp-P6L: (2S)-3-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-2-[(6E)-HEXADEC-6-ENOYLOXY]PROPYL (8E)-OCTADEC-8-ENOATE / phospholipidYM ChemComp-PO4*: PHOSPHATE ION / Phosphate
Source	staphylococcus aureus (bacteria)
Keywords	SIGNALING PROTEIN / Antibiotic resistance / beta-lactam antibiotics / MRSA / BlaR1 / MecR1 / cryo-EM / transmembrane signalling / SIGNALING PROTEIN/ANTIBIOTIC / SIGNALING PROTEIN-ANTIBIOTIC complex