1ga9: Difference between revisions

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-{{Seed}}
-[[Image:1ga9.png|left|200px]]
-<!--
+==CRYSTAL STRUCTURE OF AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH NON-BETA-LACTAMASE INHIBITOR (2, 3-(4-BENZENESULFONYL-THIOPHENE-2-SULFONYLAMINO)-PHENYLBORONIC ACID)==
-The line below this paragraph, containing "STRUCTURE_1ga9", creates the "Structure Box" on the page.
+<StructureSection load='1ga9' size='340' side='right'caption='[[1ga9]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[1ga9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GA9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GA9 FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ETP:3-(4-BENZENESULFONYL-THIOPHENE-2-SULFONYLAMINO)-PHENYLBORONIC+ACID'>ETP</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-{{STRUCTURE_1ga9|  PDB=1ga9  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ga9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ga9 OCA], [https://pdbe.org/1ga9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ga9 RCSB], [https://www.ebi.ac.uk/pdbsum/1ga9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ga9 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ga/1ga9_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ga9 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+BACKGROUND: Group I beta-lactamases are a major cause of antibiotic resistance to beta-lactams such as penicillins and cephalosporins. These enzymes are only modestly affected by classic beta-lactam-based inhibitors, such as clavulanic acid. Conversely, small arylboronic acids inhibit these enzymes at sub-micromolar concentrations. Structural studies suggest these inhibitors bind to a well-defined cleft in the group I beta-lactamase AmpC; this cleft binds the ubiquitous R1 side chain of beta-lactams. Intriguingly, much of this cleft is left unoccupied by the small arylboronic acids. RESULTS: To investigate if larger boronic acids might take advantage of this cleft, structure-guided in-parallel synthesis was used to explore new inhibitors of AmpC. Twenty-eight derivatives of the lead compound, 3-aminophenylboronic acid, led to an inhibitor with 80-fold better binding (2; K(i) 83 nM). Molecular docking suggested orientations for this compound in the R1 cleft. Based on the docking results, 12 derivatives of 2 were synthesized, leading to inhibitors with K(i) values of 60 nM and with improved solubility. Several of these inhibitors reversed the resistance of nosocomial Gram-positive bacteria, though they showed little activity against Gram-negative bacteria. The X-ray crystal structure of compound 2 in complex with AmpC was subsequently determined to 2.1 A resolution. The placement of the proximal two-thirds of the inhibitor in the experimental structure corresponds with the docked structure, but a bond rotation leads to a distinctly different placement of the distal part of the inhibitor. In the experimental structure, the inhibitor interacts with conserved residues in the R1 cleft whose role in recognition has not been previously explored. CONCLUSIONS: Combining structure-based design with in-parallel synthesis allowed for the rapid exploration of inhibitor functionality in the R1 cleft of AmpC. The resulting inhibitors differ considerably from beta-lactams but nevertheless inhibit the enzyme well. The crystal structure of 2 (K(i) 83 nM) in complex with AmpC may guide exploration of a highly conserved, largely unexplored cleft, providing a template for further design against AmpC beta-lactamase.
-===CRYSTAL STRUCTURE OF AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH NON-BETA-LACTAMASE INHIBITOR (2, 3-(4-BENZENESULFONYL-THIOPHENE-2-SULFONYLAMINO)-PHENYLBORONIC ACID)===
+Structure-based design and in-parallel synthesis of inhibitors of AmpC beta-lactamase.,Tondi D, Powers RA, Caselli E, Negri MC, Blazquez J, Costi MP, Shoichet BK Chem Biol. 2001 Jun;8(6):593-611. PMID:11410378<ref>PMID:11410378</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<!--
+</div>
-The line below this paragraph, {{ABSTRACT_PUBMED_11410378}}, adds the Publication Abstract to the page
+<div class="pdbe-citations 1ga9" style="background-color:#fffaf0;"></div>
-(as it appears on PubMed at http://www.pubmed.gov), where 11410378 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_11410378}}
+__TOC__
+</StructureSection>
-==About this Structure==
-GA9 is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GA9 OCA].
-==Reference==
-<ref group="xtra">PMID:11410378</ref><references group="xtra"/>
-[[Category: Beta-lactamase]]
 [[Category: Escherichia coli]]
-[[Category: Blazquez, J.]]
+[[Category: Large Structures]]
-[[Category: Caselli, E.]]
+[[Category: Blazquez J]]
-[[Category: Costi, M P.]]
+[[Category: Caselli E]]
-[[Category: Negri, M C.]]
+[[Category: Costi MP]]
-[[Category: Powers, R A.]]
+[[Category: Negri MC]]
-[[Category: Shoichet, B K.]]
+[[Category: Powers RA]]
-[[Category: Tondi, D.]]
+[[Category: Shoichet BK]]
-[[Category: Beta-lactamase]]
+[[Category: Tondi D]]
-[[Category: Cephalosporinase]]
-[[Category: Serine hydrolase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 14:27:59 2009''