4MYO

Crystal structure of streptogramin group A antibiotic acetyltransferase VatA from Staphylococcus aureus

Replaces:  4E8L

Summary for 4MYO

• Entry DOI: 10.2210/pdb4myo/pdb
• Related: 4HUR 4HUS
• Descriptor: Virginiamycin A acetyltransferase, MAGNESIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: structural genomics, antibiotic resistance, center for structural genomics of infectious diseases, csgid, niaid, national institute of allergy and infectious diseases, left-handed beta helix domain, xenobiotic acyltransferase (xat) family, hexapeptide repeat acyltransferase, transferase, streptogramin group a antibiotics, streptogramin a, virginiamycin, dalfopristin, acetyl coenzyme a, coenzyme a, intracellular
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 3
• Total formula weight: 73650.43

Authors

Stogios, P.J.,Minasov, G.,Dong, A.,Evdokimova, E.,Yim, V.,Krishnamoorthy, M.,Di Leo, R.,Courvalin, P.,Savchenko, A.,Anderson, W.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2013-09-27, release date: 2013-10-16, Last modification date: 2023-09-20)

Primary citation

Stogios, P.J.,Kuhn, M.L.,Evdokimova, E.,Courvalin, P.,Anderson, W.F.,Savchenko, A.
Potential for Reduction of Streptogramin A Resistance Revealed by Structural Analysis of Acetyltransferase VatA.
Antimicrob.Agents Chemother., 58:7083-7092, 2014

PubMed Abstract: Combinations of group A and B streptogramins (i.e., dalfopristin and quinupristin) are "last-resort" antibiotics for the treatment of infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Resistance to streptogramins has arisen via multiple mechanisms, including the deactivation of the group A component by the large family of virginiamycin O-acetyltransferase (Vat) enzymes. Despite the structural elucidation performed for the VatD acetyltransferase, which provided a general molecular framework for activity, a detailed characterization of the essential catalytic and antibiotic substrate-binding determinants in Vat enzymes is still lacking. We have determined the crystal structure of S. aureus VatA in apo, virginiamycin M1- and acetyl-coenzyme A (CoA)-bound forms and provide an extensive mutagenesis and functional analysis of the structural determinants required for catalysis and streptogramin A recognition. Based on an updated genomic survey across the Vat enzyme family, we identified key conserved residues critical for VatA activity that are not part of the O-acetylation catalytic apparatus. Exploiting such constraints of the Vat active site may lead to the development of streptogramin A compounds that evade inactivation by Vat enzymes while retaining binding to their ribosomal target.

PubMed: 25223995
DOI: 10.1128/AAC.03743-14

Experimental method

X-RAY DIFFRACTION (2.696 Å)