3zg0: Difference between revisions
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The | ==Crystal structure of ceftaroline acyl-PBP2a from MRSA with non- covalently bound ceftaroline and muramic acid at allosteric site obtained by cocrystallization== | ||
<StructureSection load='3zg0' size='340' side='right'caption='[[3zg0]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3zg0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_Mu50 Staphylococcus aureus subsp. aureus Mu50]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZG0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZG0 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1W8:CEFTAROLINE'>1W8</scene>, <scene name='pdbligand=AI8:CEFTAROLINE,+BOUND+FORM'>AI8</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MUR:MURAMIC+ACID'>MUR</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3zg0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zg0 OCA], [https://pdbe.org/3zg0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zg0 RCSB], [https://www.ebi.ac.uk/pdbsum/3zg0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zg0 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A0H3JPA5_STAAM A0A0H3JPA5_STAAM] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the beta-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 beta-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 beta-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to beta-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with beta-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain-a remarkable 60 A 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 beta-lactam antibiotic. The ability of an anti-MRSA beta-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second beta-lactam molecule, opens an unprecedented realm for beta-lactam antibiotic structure-based design. | |||
How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function.,Otero LH, Rojas-Altuve A, Llarrull LI, Carrasco-Lopez C, Kumarasiri M, Lastochkin E, Fishovitz J, Dawley M, Hesek D, Lee M, Johnson JW, Fisher JF, Chang M, Mobashery S, Hermoso JA Proc Natl Acad Sci U S A. 2013 Oct 1. PMID:24085846<ref>PMID:24085846</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3zg0" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Penicillin-binding protein 3D structures|Penicillin-binding protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus subsp. aureus Mu50]] | |||
[[Category: Hermoso JA]] | |||
[[Category: Otero LH]] | |||
[[Category: Rojas-Altuve A]] | |||
Latest revision as of 14:01, 20 December 2023
Crystal structure of ceftaroline acyl-PBP2a from MRSA with non- covalently bound ceftaroline and muramic acid at allosteric site obtained by cocrystallizationCrystal structure of ceftaroline acyl-PBP2a from MRSA with non- covalently bound ceftaroline and muramic acid at allosteric site obtained by cocrystallization
Structural highlights
FunctionPublication Abstract from PubMedThe expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the beta-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 beta-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 beta-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to beta-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with beta-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain-a remarkable 60 A 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 beta-lactam antibiotic. The ability of an anti-MRSA beta-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second beta-lactam molecule, opens an unprecedented realm for beta-lactam antibiotic structure-based design. How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function.,Otero LH, Rojas-Altuve A, Llarrull LI, Carrasco-Lopez C, Kumarasiri M, Lastochkin E, Fishovitz J, Dawley M, Hesek D, Lee M, Johnson JW, Fisher JF, Chang M, Mobashery S, Hermoso JA Proc Natl Acad Sci U S A. 2013 Oct 1. PMID:24085846[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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