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| | ==SHV-1 beta-lactamase complex with LN1-255== | | ==SHV-1 beta-lactamase complex with LN1-255== |
| - | <StructureSection load='3d4f' size='340' side='right' caption='[[3d4f]], [[Resolution|resolution]] 1.55Å' scene=''> | + | <StructureSection load='3d4f' size='340' side='right'caption='[[3d4f]], [[Resolution|resolution]] 1.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3d4f]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pneumoniae"_(schroeter_1886)_flugge_1886 "bacillus pneumoniae" (schroeter 1886) flugge 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D4F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3D4F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3d4f]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D4F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D4F FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LN1:(3R)-4-{[(3,4-DIHYDROXYPHENYL)ACETYL]OXY}-N-(2-FORMYLINDOLIZIN-3-YL)-3-SULFINO-D-VALINE'>LN1</scene>, <scene name='pdbligand=MA4:CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE'>MA4</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]] 1.55Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1shv|1shv]], [[1ga0|1ga0]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LN1:(3R)-4-{[(3,4-DIHYDROXYPHENYL)ACETYL]OXY}-N-(2-FORMYLINDOLIZIN-3-YL)-3-SULFINO-D-VALINE'>LN1</scene>, <scene name='pdbligand=MA4:CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE'>MA4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">bla, shv1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=573 "Bacillus pneumoniae" (Schroeter 1886) Flugge 1886])</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=3d4f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d4f OCA], [https://pdbe.org/3d4f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d4f RCSB], [https://www.ebi.ac.uk/pdbsum/3d4f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d4f 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>
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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=3d4f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d4f OCA], [http://pdbe.org/3d4f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3d4f RCSB], [http://www.ebi.ac.uk/pdbsum/3d4f PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/BLA1_KLEPN BLA1_KLEPN] |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d4/3d4f_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d4/3d4f_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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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: Klebsiella pneumoniae]] |
| - | [[Category: Akker, F van den]] | + | [[Category: Large Structures]] |
| - | [[Category: Bethel, C R]] | + | [[Category: Bethel CR]] |
| - | [[Category: Bonomo, R A]] | + | [[Category: Bonomo RA]] |
| - | [[Category: Buynak, J D]] | + | [[Category: Buynak JD]] |
| - | [[Category: Hujer, A M]] | + | [[Category: Hujer AM]] |
| - | [[Category: Pattanaik, P]] | + | [[Category: Pattanaik P]] |
| - | [[Category: Antibiotic resistance]] | + | [[Category: Van den Akker F]] |
| - | [[Category: Beta-lactamase inhibitor]]
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| - | [[Category: Drug design]]
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| - | [[Category: Hydrolase]]
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| Structural highlights
Function
BLA1_KLEPN
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
In an effort to devise strategies for overcoming bacterial beta-lactamases, we studied LN-1-255, a 6-alkylidene-2'-substituted penicillin sulfone inhibitor. By possessing a catecholic functionality that resembles a natural bacterial siderophore, LN-1-255 is unique among beta-lactamase inhibitors. LN-1-255 combined with piperacillin was more potent against Escherichia coli DH10B strains bearing bla(SHV) extended-spectrum and inhibitor-resistant beta-lactamases than an equivalent amount of tazobactam and piperacillin. In addition, LN-1-255 significantly enhanced the activity of ceftazidime and cefpirome against extended-spectrum cephalosporin and Sme-1 containing carbapenem-resistant clinical strains. LN-1-255 inhibited SHV-1 and SHV-2 beta-lactamases with nm affinity (K(I) = 110 +/- 10 and 100 +/- 10 nm, respectively). When LN-1-255 inactivated SHV beta-lactamases, a single intermediate was detected by mass spectrometry. The crystal structure of LN-1-255 in complex with SHV-1 was determined at 1.55A resolution. Interestingly, this novel inhibitor forms a bicyclic aromatic intermediate with its carbonyl oxygen pointing out of the oxyanion hole and forming hydrogen bonds with Lys-234 and Ser-130 in the active site. Electron density for the "tail" of LN-1-255 is less ordered and modeled in two conformations. Both conformations have the LN-1-255 carboxyl group interacting with Arg-244, yet the remaining tails of the two conformations diverge. The observed presence of the bicyclic aromatic intermediate with its carbonyl oxygen positioned outside of the oxyanion hole provides a rationale for the stability of this inhibitory intermediate. The 2'-substituted penicillin sulfone, LN-1-255, is proving to be an important lead compound for novel beta-lactamase inhibitor design.
Strategic design of an effective beta-lactamase inhibitor: LN-1-255, a 6-alkylidene-2'-substituted penicillin sulfone.,Pattanaik P, Bethel CR, Hujer AM, Hujer KM, Distler AM, Taracila M, Anderson VE, Fritsche TR, Jones RN, Pagadala SR, van den Akker F, Buynak JD, Bonomo RA J Biol Chem. 2009 Jan 9;284(2):945-53. Epub 2008 Oct 27. PMID:18955486[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pattanaik P, Bethel CR, Hujer AM, Hujer KM, Distler AM, Taracila M, Anderson VE, Fritsche TR, Jones RN, Pagadala SR, van den Akker F, Buynak JD, Bonomo RA. Strategic design of an effective beta-lactamase inhibitor: LN-1-255, a 6-alkylidene-2'-substituted penicillin sulfone. J Biol Chem. 2009 Jan 9;284(2):945-53. Epub 2008 Oct 27. PMID:18955486 doi:10.1074/jbc.M806833200
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