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| <StructureSection load='4kz3' size='340' side='right'caption='[[4kz3]], [[Resolution|resolution]] 1.67Å' scene=''> | | <StructureSection load='4kz3' size='340' side='right'caption='[[4kz3]], [[Resolution|resolution]] 1.67Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
- | <table><tr><td colspan='2'>[[4kz3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KZ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KZ3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4kz3]] 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=4KZ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KZ3 FirstGlance]. <br> |
- | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1U1:5-CHLORO-3-SULFAMOYLTHIOPHENE-2-CARBOXYLIC+ACID'>1U1</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.67Å</td></tr> |
- | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4kz4|4kz4]], [[4kz5|4kz5]], [[4kz6|4kz6]], [[4kz7|4kz7]], [[4kz8|4kz8]], [[4kz9|4kz9]], [[4kza|4kza]], [[4kzb|4kzb]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1U1:5-CHLORO-3-SULFAMOYLTHIOPHENE-2-CARBOXYLIC+ACID'>1U1</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
- | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ampA, ampC, b4150, JW4111 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</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=4kz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kz3 OCA], [https://pdbe.org/4kz3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kz3 RCSB], [https://www.ebi.ac.uk/pdbsum/4kz3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kz3 ProSAT]</span></td></tr> |
- | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr>
| + | |
- | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4kz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kz3 OCA], [http://pdbe.org/4kz3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4kz3 RCSB], [http://www.ebi.ac.uk/pdbsum/4kz3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4kz3 ProSAT]</span></td></tr> | + | |
| </table> | | </table> |
| == Function == | | == Function == |
- | [[http://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI]] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins. | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| ==See Also== | | ==See Also== |
- | *[[Beta-lactamase|Beta-lactamase]] | + | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
- | [[Category: Beta-lactamase]] | + | [[Category: Escherichia coli K-12]] |
- | [[Category: Ecoli]]
| + | |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
- | [[Category: Barelier, S]] | + | [[Category: Barelier S]] |
- | [[Category: Eidam, O]] | + | [[Category: Eidam O]] |
- | [[Category: Fish, I]] | + | [[Category: Fish I]] |
- | [[Category: Shoichet, B K]] | + | [[Category: Shoichet BK]] |
- | [[Category: Ampc beta-lactamase]]
| + | |
- | [[Category: Cephalosporinase]]
| + | |
- | [[Category: Class c]]
| + | |
- | [[Category: Hydrolase]]
| + | |
- | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| Structural highlights
Function
AMPC_ECOLI This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
Publication Abstract from PubMed
Most libraries for fragment-based drug discovery are restricted to 1,000 to 10,000 compounds, but over 700,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and whether a computational screen can pragmatically prioritize them, is debated. To investigate this question, a 1281 fragment library was screened by Nuclear Magnetic Resonance (NMR) against AmpC beta-lactamase and hits confirmed by Surface Plasmon Resonance (SPR). Nine hits with novel chemotypes were confirmed biochemically with KI values from 0.2 to low mM. We also computationally docked 290,000 purchasable fragments with chemotypes unrepresented in the empirical library, finding ten that had KI values from 0.03 to low mM. Though less novel than those discovered by NMR, the docking-derived fragments filled chemotype holes from the empirical library. Crystal structures of nine of the fragments in complex with AmpC beta-lactamase revealed new binding sites, and explained the relatively high-affinity of the docking-derived fragments. The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules, would minimally demand a library of over 32,000 fragments. Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.
Increasing chemical space coverage by combining empirical and computational fragment screens.,Barelier S, Eidam O, Fish I, Hollander J, Figaroa F, Nachane R, Irwin JJ, Shoichet BK, Siegal GD ACS Chem Biol. 2014 May 7. PMID:24807704[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Barelier S, Eidam O, Fish I, Hollander J, Figaroa F, Nachane R, Irwin JJ, Shoichet BK, Siegal GD. Increasing chemical space coverage by combining empirical and computational fragment screens. ACS Chem Biol. 2014 May 7. PMID:24807704 doi:http://dx.doi.org/10.1021/cb5001636
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