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| <StructureSection load='6vim' size='340' side='right'caption='[[6vim]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='6vim' size='340' side='right'caption='[[6vim]], [[Resolution|resolution]] 2.00Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[6vim]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_fluorescens_putidus"_flugge_1886 "bacillus fluorescens putidus" flugge 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VIM OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VIM FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VIM FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PBC:PHENYL+BORONIC+ACID'>PBC</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]] 2Å</td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mdlA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=303 "Bacillus fluorescens putidus" Flugge 1886])</td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PBC:PHENYL+BORONIC+ACID'>PBC</scene></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mandelate_racemase Mandelate racemase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.1.2.2 5.1.2.2] </span></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=6vim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vim OCA], [https://pdbe.org/6vim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vim RCSB], [https://www.ebi.ac.uk/pdbsum/6vim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vim ProSAT]</span></td></tr> |
| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vim OCA], [http://pdbe.org/6vim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vim RCSB], [http://www.ebi.ac.uk/pdbsum/6vim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vim ProSAT]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Boronic acids have been successfully employed as inhibitors of hydrolytic enzymes. Typically, an enzymatic nucleophile catalyzing hydrolysis adds to the electrophilic boron atom forming a tetrahedral species that mimics the intermediate(s)/transition state(s) for the hydrolysis reaction. We show that para-substituted phenylboronic acids (PBAs) are potent competitive inhibitors of mandelate racemase (MR), an enzyme that catalyzes a 1,1-proton transfer rather than a hydrolysis reaction. The Ki value for PBA was 1.8 +/- 0.1 muM, and p-Cl-PBA exhibited the most potent inhibition (Ki = 81 +/- 4 nM), exceeding the binding affinity of the substrate by approximately 4 orders of magnitude. Isothermal titration calorimetric studies with the wild-type, K166M, and H297N MR variants indicated that, of the two Bronsted acid-base catalysts Lys 166 and His 297, the former made the greater contribution to inhibitor binding. The X-ray crystal structure of the MR.PBA complex revealed the presence of multiple H-bonds between the boronic acid hydroxyl groups and the side chains of active site residues, as well as formation of a His 297 N(epsilon2)-B dative bond. The dramatic upfield change in chemical shift of 27.2 ppm in the solution-phase (11)B nuclear magnetic resonance spectrum accompanying binding of PBA by MR was consistent with an sp(3)-hybridized boron, which was also supported by density-functional theory calculations. These unprecedented findings suggest that, beyond substituting boron at carbon centers participating in hydrolysis reactions, substitution of boron at the acidic carbon center of a substrate furnishes a new approach for generating inhibitors of enzymes catalyzing the deprotonation of carbon acid substrates.
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| Potent Inhibition of Mandelate Racemase by Boronic Acids: Boron as a Mimic of a Carbon Acid Center.,Sharma AN, Grandinetti L, Johnson ER, St Maurice M, Bearne SL Biochemistry. 2020 Aug 25;59(33):3026-3037. doi: 10.1021/acs.biochem.0c00478., Epub 2020 Aug 10. PMID:32786399<ref>PMID:32786399</ref>
| | ==See Also== |
| | | *[[Mandelate racemase|Mandelate racemase]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 6vim" style="background-color:#fffaf0;"></div>
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| == References == | |
| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Bacillus fluorescens putidus flugge 1886]]
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| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Mandelate racemase]]
| | [[Category: Bearne SL]] |
| [[Category: Bearne, S L]] | | [[Category: Grandinetti L]] |
| [[Category: Grandinetti, L]] | | [[Category: Sharma AN]] |
| [[Category: Maurice, M St]]
| | [[Category: St Maurice M]] |
| [[Category: Sharma, A N]] | |
| [[Category: Boronate]] | |
| [[Category: Inhibitor]]
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| [[Category: Isomerase]]
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| [[Category: Isomerase-inhibitor complex]]
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