4lv3: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| (6 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==AmpC beta-lactamase in complex with (3,5-di-tert-butylphenyl) boronic acid== | ==AmpC beta-lactamase in complex with (3,5-di-tert-butylphenyl) boronic acid== | ||
<StructureSection load='4lv3' size='340' side='right' caption='[[4lv3]], [[Resolution|resolution]] 1.42Å' scene=''> | <StructureSection load='4lv3' size='340' side='right'caption='[[4lv3]], [[Resolution|resolution]] 1.42Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4lv3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LV3 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4lv3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LV3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LV3 FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.42Å</td></tr> | ||
<tr><td class="sblockLbl"><b>[[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=25N:(3,5-DI-TERT-BUTYLPHENYL)BORONIC+ACID'>25N</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=4lv3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lv3 OCA], [https://pdbe.org/4lv3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lv3 RCSB], [https://www.ebi.ac.uk/pdbsum/4lv3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lv3 ProSAT]</span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </table> | ||
<table> | == Function == | ||
[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Chemical probes that form a covalent bond with a protein target often show enhanced selectivity, potency and utility for biological studies. Despite these advantages, protein-reactive compounds are usually avoided in high-throughput screening campaigns. Here we describe a general method (DOCKovalent) for screening large virtual libraries of electrophilic small molecules. We apply this method prospectively to discover reversible covalent fragments that target distinct protein nucleophiles, including the catalytic serine of AmpC beta-lactamase and noncatalytic cysteines in RSK2, MSK1 and JAK3 kinases. We identify submicromolar to low-nanomolar hits with high ligand efficiency, cellular activity and selectivity, including what are to our knowledge the first reported reversible covalent inhibitors of JAK3. Crystal structures of inhibitor complexes with AmpC and RSK2 confirm the docking predictions and guide further optimization. As covalent virtual screening may have broad utility for the rapid discovery of chemical probes, we have made the method freely available through an automated web server (http://covalent.docking.org/). | |||
Covalent docking of large libraries for the discovery of chemical probes.,London N, Miller RM, Krishnan S, Uchida K, Irwin JJ, Eidam O, Gibold L, Cimermancic P, Bonnet R, Shoichet BK, Taunton J Nat Chem Biol. 2014 Oct 26. doi: 10.1038/nchembio.1666. PMID:25344815<ref>PMID:25344815</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4lv3" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Escherichia coli K-12]] | ||
[[Category: Large Structures]] | |||
[[Category: Eidam O]] | |||
[[Category: London N]] | |||
[[Category: Shoichet BK]] | |||
[[Category: | |||
[[Category: | |||
[[Category: | |||
[[Category: | |||
Latest revision as of 19:26, 20 September 2023
AmpC beta-lactamase in complex with (3,5-di-tert-butylphenyl) boronic acidAmpC beta-lactamase in complex with (3,5-di-tert-butylphenyl) boronic acid
Structural highlights
FunctionAMPC_ECOLI This protein is a serine beta-lactamase with a substrate specificity for cephalosporins. Publication Abstract from PubMedChemical probes that form a covalent bond with a protein target often show enhanced selectivity, potency and utility for biological studies. Despite these advantages, protein-reactive compounds are usually avoided in high-throughput screening campaigns. Here we describe a general method (DOCKovalent) for screening large virtual libraries of electrophilic small molecules. We apply this method prospectively to discover reversible covalent fragments that target distinct protein nucleophiles, including the catalytic serine of AmpC beta-lactamase and noncatalytic cysteines in RSK2, MSK1 and JAK3 kinases. We identify submicromolar to low-nanomolar hits with high ligand efficiency, cellular activity and selectivity, including what are to our knowledge the first reported reversible covalent inhibitors of JAK3. Crystal structures of inhibitor complexes with AmpC and RSK2 confirm the docking predictions and guide further optimization. As covalent virtual screening may have broad utility for the rapid discovery of chemical probes, we have made the method freely available through an automated web server (http://covalent.docking.org/). Covalent docking of large libraries for the discovery of chemical probes.,London N, Miller RM, Krishnan S, Uchida K, Irwin JJ, Eidam O, Gibold L, Cimermancic P, Bonnet R, Shoichet BK, Taunton J Nat Chem Biol. 2014 Oct 26. doi: 10.1038/nchembio.1666. PMID:25344815[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||