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4e3i

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==Crystal structure of AmpC beta-lactamase in complex with a designed 3-carboxyl benzyl sulfonamide boronic acid inhibitor==
==Crystal structure of AmpC beta-lactamase in complex with a designed 3-carboxyl benzyl sulfonamide boronic acid inhibitor==
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<StructureSection load='4e3i' size='340' side='right' caption='[[4e3i]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
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<StructureSection load='4e3i' size='340' side='right'caption='[[4e3i]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4e3i]] 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=4E3I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E3I FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4e3i]] 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=4E3I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E3I FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0N3:3-({[(DIHYDROXYBORANYL)METHYL]SULFAMOYL}METHYL)BENZOIC+ACID'>0N3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4e3j|4e3j]], [[4e3k|4e3k]], [[4e3l|4e3l]], [[4e3m|4e3m]], [[4e3n|4e3n]], [[4e3o|4e3o]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0N3:3-({[(DIHYDROXYBORANYL)METHYL]SULFAMOYL}METHYL)BENZOIC+ACID'>0N3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4e3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e3i OCA], [https://pdbe.org/4e3i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e3i RCSB], [https://www.ebi.ac.uk/pdbsum/4e3i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e3i ProSAT]</span></td></tr>
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<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>
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<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=4e3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e3i OCA], [http://pdbe.org/4e3i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4e3i RCSB], [http://www.ebi.ac.uk/pdbsum/4e3i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4e3i ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI]] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
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[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Fragment-based design was used to guide derivatization of a lead series of beta-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K(i) of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with beta-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome beta-lactamase-based resistance, a key clinical challenge.
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Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo.,Eidam O, Romagnoli C, Dalmasso G, Barelier S, Caselli E, Bonnet R, Shoichet BK, Prati F Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17448-53. doi:, 10.1073/pnas.1208337109. Epub 2012 Oct 5. PMID:23043117<ref>PMID:23043117</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4e3i" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Beta-lactamase|Beta-lactamase]]
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*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Beta-lactamase]]
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[[Category: Escherichia coli K-12]]
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[[Category: Ecoli]]
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[[Category: Large Structures]]
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[[Category: Eidam, O]]
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[[Category: Eidam O]]
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[[Category: Shoichet, B K]]
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[[Category: Shoichet BK]]
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[[Category: Ampc beta-lactamase]]
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[[Category: Cephalosporinase]]
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[[Category: Class c]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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Current revision

Crystal structure of AmpC beta-lactamase in complex with a designed 3-carboxyl benzyl sulfonamide boronic acid inhibitor

PDB ID 4e3i

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