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==PENICILLIN-BINDING PROTEIN 1B (PBP-1B) IN COMPLEX WITH AN ALKYL BORONATE (ZA2)== | |||
<StructureSection load='2y2h' size='340' side='right'caption='[[2y2h]], [[Resolution|resolution]] 1.96Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2y2h]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptococcus_pneumoniae_R6 Streptococcus pneumoniae R6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y2H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Y2H 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]] 1.96Å</td></tr> | |||
- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZA2:[(2-CHLOROPHENYL)CARBONYLAMINO]METHYL-TRIHYDROXY-BORON'>ZA2</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=2y2h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y2h OCA], [https://pdbe.org/2y2h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2y2h RCSB], [https://www.ebi.ac.uk/pdbsum/2y2h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2y2h ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q7CRA4_STRR6 Q7CRA4_STRR6] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
beta-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis. Many pathogens express drug-insensitive PBPs rendering beta-lactams ineffective, revealing a need for new types of PBP inhibitors active against resistant strains. We have identified alkyl boronic acids that are active against pathogens including methicillin-resistant S. aureus (MRSA). The crystal structures of PBP1b complexed to eleven different alkyl boronates demonstrate that in vivo efficacy correlates with the mode of inhibitor side chain binding. Staphylococcal membrane analyses reveal that the most potent alkyl boronate targets PBP1, an autolysis system regulator, and PBP2a, a low beta-lactam affinity enzyme. This work demonstrates the potential of boronate-based PBP-inhibitors for circumventing beta-lactam resistance, and opens avenues for the development of novel antibiotics that target Gram-positive pathogens. | |||
Structure-guided design of cell wall biosynthesis inhibitors that overcome beta-lactam resistance in Staphylococcus aureus (MRSA).,Contreras-Martel C, Amoroso A, Woon EC, Zervosen A, Inglis S, Martins A, Verlaine O, Rydzik A, Job V, Luxen A, Joris B, Schofield CJ, Dessen A ACS Chem Biol. 2011 Jul 6. PMID:21732689<ref>PMID:21732689</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2y2h" 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: Streptococcus pneumoniae R6]] | ||
[[Category: Amoroso A]] | |||
== | [[Category: Contreras-Martel C]] | ||
< | [[Category: Dessen A]] | ||
[[Category: Streptococcus pneumoniae]] | [[Category: Inglis S]] | ||
[[Category: Amoroso | [[Category: Job V]] | ||
[[Category: Contreras-Martel | [[Category: Joris B]] | ||
[[Category: Dessen | [[Category: Luxen A]] | ||
[[Category: Inglis | [[Category: Martins A]] | ||
[[Category: Job | [[Category: Rydzik A]] | ||
[[Category: Joris | [[Category: Schofield CJ]] | ||
[[Category: Luxen | [[Category: Verlaine O]] | ||
[[Category: Martins | [[Category: Woon EC]] | ||
[[Category: Rydzik | [[Category: Zervosen A]] | ||
[[Category: Schofield | |||
[[Category: Verlaine | |||
[[Category: Woon | |||
[[Category: Zervosen | |||
Latest revision as of 13:44, 20 December 2023
PENICILLIN-BINDING PROTEIN 1B (PBP-1B) IN COMPLEX WITH AN ALKYL BORONATE (ZA2)PENICILLIN-BINDING PROTEIN 1B (PBP-1B) IN COMPLEX WITH AN ALKYL BORONATE (ZA2)
Structural highlights
FunctionPublication Abstract from PubMedbeta-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis. Many pathogens express drug-insensitive PBPs rendering beta-lactams ineffective, revealing a need for new types of PBP inhibitors active against resistant strains. We have identified alkyl boronic acids that are active against pathogens including methicillin-resistant S. aureus (MRSA). The crystal structures of PBP1b complexed to eleven different alkyl boronates demonstrate that in vivo efficacy correlates with the mode of inhibitor side chain binding. Staphylococcal membrane analyses reveal that the most potent alkyl boronate targets PBP1, an autolysis system regulator, and PBP2a, a low beta-lactam affinity enzyme. This work demonstrates the potential of boronate-based PBP-inhibitors for circumventing beta-lactam resistance, and opens avenues for the development of novel antibiotics that target Gram-positive pathogens. Structure-guided design of cell wall biosynthesis inhibitors that overcome beta-lactam resistance in Staphylococcus aureus (MRSA).,Contreras-Martel C, Amoroso A, Woon EC, Zervosen A, Inglis S, Martins A, Verlaine O, Rydzik A, Job V, Luxen A, Joris B, Schofield CJ, Dessen A ACS Chem Biol. 2011 Jul 6. PMID:21732689[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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