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1h8y

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[[Image:1h8y.gif|left|200px]]<br /><applet load="1h8y" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1h8y, resolution 2.0&Aring;" />
 
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'''CRYSTAL STRUCTURE OF THE CLASS D BETA-LACTAMASE OXA-13 IN COMPLEX WITH MEROPENEM'''<br />
 
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==Overview==
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==Crystal structure of the class D beta-lactamase OXA-13 in complex with meropenem==
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The therapeutic problems posed by class D beta-lactamases, a family of, serine enzymes that hydrolyse beta-lactam antibiotics following an, acylation-deacylation mechanism, are increased by the very low level of, sensitivity of these enzymes to beta-lactamase inhibitors. To gain, structural and mechanistic insights to aid the design of new inhibitors, we have determined the crystal structure of OXA-13 from Pseudomonas, aeruginosa in the apo form and in complex with the carbapenem meropenem., The native form consisted of a dimer displaying an overall organisation, similar to that found in the closely related enzyme OXA-10. In the, acyl-enzyme complex, the positioning of the antibiotic appeared to be, ensured mainly by (i) the covalent acyl bond and (ii) a strong salt-bridge, involving the carboxylate moiety of the drug. Comparison of the structures, of OXA-13 in the apo form and in complex with meropenem revealed an, unsuspected flexibility in the region of the essential serine 115 residue, with possible consequences for the catalytic properties of the enzyme. In, the apo form, the Ser115 side-chain is oriented outside the active site, whereas the general base Lys70 adopts a conformation that seems to be, incompatible with the activation of the catalytic water molecule required, for the deacylation step. In the OXA-13:meropenem complex, a 3.5 A, movement of the backbone of the 114-116 loop towards the side-chain of, Lys70 was observed, which seems to be driven by a displacement of the, neighbouring 91-104 loop and which results in the repositioning of the, side-chain hydroxyl group of Ser115 toward the catalytic centre., Concomitantly, the side-chain of Lys70 is forced to curve in the direction, of the deacylating water molecule, which is then strongly bound and, activated by this residue. However, a distance of ca 5 A separates the, catalytic water molecule from the acyl carbonyl group of meropenem, a, structural feature that accounts for the inhibition of OXA-13 by this, drug. Finally, the low level of penicillinase activity revealed by the, kinetic analysis of OXA-13 could be related to the specific presence in, position 73 of a serine residue located close to the general base Lys70, which results in a decrease of the number of hydrogen-bonding interactions, stabilising the catalytic water molecule.
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<StructureSection load='1h8y' size='340' side='right'caption='[[1h8y]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1h8y]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H8Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H8Y FirstGlance]. <br>
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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]] 2&#8491;</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=MER:(4R,5S)-3-{[(3S,5S)-5-(DIMETHYLCARBAMOYL)PYRROLIDIN-3-YL]SULFANYL}-5-[(2S,3R)-3-HYDROXY-1-OXOBUTAN-2-YL]-4-METHYL-4,5-DIHYDRO-1H-PYRROLE-2-CARBOXYLIC+ACID'>MER</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=1h8y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h8y OCA], [https://pdbe.org/1h8y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h8y RCSB], [https://www.ebi.ac.uk/pdbsum/1h8y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h8y ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/Q51400_PSEAI Q51400_PSEAI]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h8/1h8y_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1h8y ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1H8Y is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa] with SO4 and MER as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Sites: <scene name='pdbsite=AC1:Mer Binding Site For Chain A'>AC1</scene> and <scene name='pdbsite=AC2:Mer Binding Site For Chain B'>AC2</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1H8Y OCA].
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*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Crystal structures of the class D beta-lactamase OXA-13 in the native form and in complex with meropenem., Pernot L, Frenois F, Rybkine T, L'Hermite G, Petrella S, Delettre J, Jarlier V, Collatz E, Sougakoff W, J Mol Biol. 2001 Jul 20;310(4):859-74. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11453693 11453693]
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[[Category: Large Structures]]
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[[Category: Beta-lactamase]]
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[[Category: Pseudomonas aeruginosa]]
[[Category: Pseudomonas aeruginosa]]
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[[Category: Single protein]]
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[[Category: Collatz E]]
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[[Category: Collatz, E.]]
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[[Category: Delettre J]]
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[[Category: Delettre, J.]]
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[[Category: Frenois F]]
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[[Category: Frenois, F.]]
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[[Category: Jarlier V]]
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[[Category: Hermite, G.L.]]
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[[Category: L'Hermite G]]
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[[Category: Jarlier, V.]]
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[[Category: Pernot L]]
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[[Category: Pernot, L.]]
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[[Category: Petrella S]]
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[[Category: Petrella, S.]]
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[[Category: Rybkine T]]
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[[Category: Rybkine, T.]]
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[[Category: Sougakoff W]]
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[[Category: Sougakoff, W.]]
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[[Category: MER]]
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[[Category: SO4]]
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[[Category: acyl-enzyme]]
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[[Category: beta-lactamase]]
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[[Category: class d]]
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[[Category: hydrolase]]
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[[Category: meropenem]]
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[[Category: oxa-13]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 16:08:47 2007''
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Current revision

Crystal structure of the class D beta-lactamase OXA-13 in complex with meropenem

PDB ID 1h8y

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