6o9s | pdb_00006o9s

Crystal structure of Staphylococcus aureus MecR1 antibiotic-sensor domain in complex with avibactam

spinqualitylabelsall models 6o9s, resolution 1.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6o9s is a 1 chain structure with sequence from Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.59Å Ligands: NXL, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MECR_STAAU Penicillin-interactive protein and potential antirepressor. Publication Abstract from PubMed Methicillin-resistant Staphylococcus aureus (MRSA) infections cause significant mortality and morbidity globally. MRSA resistance to beta-lactam antibiotics is mediated by two divergons that control levels of a beta-lactamase, PC1, and a penicillin-binding protein poorly acylated by beta-lactam antibiotics, PBP2a. Expression of genes encoding these proteins is controlled by two integral membrane proteins, BlaR1 and MecR1, which both have an extracellular beta-lactam-binding sensor domain. Here, we solved the X-ray crystallographic structures of the BlaR1 and MecR1 sensor domains in complex with avibactam, a diazabicyclooctane beta-lactamase inhibitor at 1.6-2.0 A resolution. Additionally, we show that S. aureus SF8300, a clinically relevant strain from the USA300 clone of MRSA, responds to avibactam by up-regulating the expression of the blaZ and pbp2a antibiotic-resistance genes, encoding PC1 and PBP2a, respectively. The BlaR1-avibactam structure of the carbamoyl-enzyme intermediate revealed that avibactam is bound to the active-site serine in two orientations approximately 180 degrees to each other. Although a physiological role of the observed alternative pose remains to be validated, our structural results hint at the presence of a secondary sulfate-binding pocket that could be exploited in the design of future inhibitors of BlaR1/MecR1 sensor domains or the structurally similar class D beta-lactamases. The MecR1-avibactam structure adopted a singular avibactam orientation similar to one of the two states observed in the BlaR1-avibactam structure. Given avibactam up-regulates expression of blaZ and pbp2a antibiotic resistance genes, we suggest further consideration and research is needed to explore what effects administering beta-lactam-avibactam combinations have on treating MRSA infections. Structural analysis of avibactam-mediated activation of the bla and mec divergons in methicillin-resistant Staphylococcus aureus.,Alexander JAN, Radaeva M, King DT, Chambers HF, Cherkasov A, Chatterjee SS, Strynadka NCJ J Biol Chem. 2020 Aug 7;295(32):10870-10884. doi: 10.1074/jbc.RA120.013029. Epub , 2020 Jun 9. PMID:32518158 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA