ArticleProceedings of the National Academy of Sciences of the United States of America2013
How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers.
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Who cites it
140 citing papers in PubMed, 260 citations in OpenAlex.
- Molecular Docking of Natural Products: Critical Appraisal of Current Methodology and Practical Guidelines.Molecules (Basel, Switzerland) · 2026Review
- Discovery of a Novel Benzothiophene Inhibitor of Penicillin-Binding Protein 2 with Potent Gram-Positive Activity.Antibiotics (Basel, Switzerland) · 2026Article
- An Achilles' heel for methicillin-resistantAntimicrobial agents and chemotherapy · 2026Review
- Design of a cyclic peptide targeting intracellular Staphylococcus aureus.Molecular biomedicine · 2026Article
- Early cell-wall stress signatures enable 20-min ATR-FTIR discrimination of MRSA and MSSA.Scientific reports · 2026Article
- Antimicrobial quinoline triazoles: synthesis, docking, and dynamic simulation studies against biofilm-associated infections.Molecular diversity · 2026Article
- Discovery of a tetrazole-thiourea derivative as a potential active agent against multidrug-resistant Staphylococcus aureus and Mycobacterium tuberculosis.Pharmacological reports : PR · 2026Article
- Molecular Insights into the β‑Lactam α‑Methyl Modulation ofACS omega · 2026Article
- Identification of Potential Candidates with Antimicrobial Activity Against Antibiotic-ResistantInternational journal of molecular sciences · 2026Article
- Article
- Pharmacokinetics, molecular docking, and molecular dynamics simulation unveil novel lichen-derived scaffolds targeting PBP2a MRSA.Frontiers in bioinformatics · 2026Article
- Phytochemical diversity and therapeutic potential ofFrontiers in pharmacology · 2026Review
- A comprehensive review of emerging therapeutic strategies against methicillin-resistantFrontiers in microbiology · 2026Review
- Resistance to Allosteric Inhibitors.Journal of molecular biology · 2025Review
- Rapid deprotection and purification of ceftaroline free base from its phosphoramidate prodrug.Journal of medical microbiology · 2025Article
- Review
- Structural insights into full-length human fascin1: a target for cancer treatment.Acta crystallographica. Section F, Structural biology communications · 2025Article
- Phenyl urea based adjuvants for β-lactam antibiotics against methicillin resistant Staphylococcus aureus.Bioorganic & medicinal chemistry letters · 2025Article
- Phytochemistry, Antibacterial and Antioxidant Activities of Grewia lasiocarpa E. Mey. Ex Harv. Fungal Endophytes: A Computational and Experimental Validation Study.Chemistry & biodiversity · 2025Article
- Unveiling the synergistic power of 3-hydrazinoquinoxaline-2-thiol and vancomycin against MRSA: AnBiomolecules & biomedicine · 2025Article
80 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The high-molecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that comprises the bacterial cell wall. In bacteria susceptible to β-lactam antibiotics, the transpeptidase activity of their penicillin binding proteins (PBPs) is lost as a result of irreversible acylation of an active site serine by the β-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to β-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with β-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain--a remarkable 60 Å distant from the DD-transpeptidase active site--discovered by crystallographic analysis of a soluble construct of PBP2a. When this allosteric site is occupied, a multiresidue conformational change culminates in the opening of the active site to permit substrate entry. This same crystallographic analysis also reveals the identity of three allosteric ligands: muramic acid (a saccharide component of the peptidoglycan), the cell wall peptidoglycan, and ceftaroline, a recently approved anti-MRSA β-lactam antibiotic. The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second β-lactam molecule, opens an unprecedented realm for β-lactam antibiotic structure-based design.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.