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| | ==Human Aldose Reductase complexed with a ligand with an IDD structure (2) at 1.07 A.== | | ==Human Aldose Reductase complexed with a ligand with an IDD structure (2) at 1.07 A.== |
| - | <StructureSection load='4ys1' size='340' side='right' caption='[[4ys1]], [[Resolution|resolution]] 1.07Å' scene=''> | + | <StructureSection load='4ys1' size='340' side='right'caption='[[4ys1]], [[Resolution|resolution]] 1.07Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ys1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YS1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YS1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ys1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YS1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YS1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4G7:3-({[2-(CARBOXYMETHOXY)-4-FLUOROBENZOYL]AMINO}METHYL)BENZOIC+ACID'>4G7</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4G7:3-({[2-(CARBOXYMETHOXY)-4-FLUOROBENZOYL]AMINO}METHYL)BENZOIC+ACID'>4G7</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1us0|1us0]], [[4puu|4puu]], [[4puw|4puw]], [[4q7b|4q7b]], [[4qbx|4qbx]], [[4qr6|4qr6]], [[4rpq|4rpq]]</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=4ys1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ys1 OCA], [https://pdbe.org/4ys1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ys1 RCSB], [https://www.ebi.ac.uk/pdbsum/4ys1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ys1 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1B1, ALDR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] </span></td></tr>
| + | |
| - | <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=4ys1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ys1 OCA], [http://pdbe.org/4ys1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ys1 RCSB], [http://www.ebi.ac.uk/pdbsum/4ys1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ys1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ALDR_HUMAN ALDR_HUMAN]] Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies. | + | [https://www.uniprot.org/uniprot/ALDR_HUMAN ALDR_HUMAN] Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4ys1" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4ys1" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Aldose reductase 3D structures|Aldose reductase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aldehyde reductase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Heine, A]] | + | [[Category: Heine A]] |
| - | [[Category: Klebe, G]] | + | [[Category: Klebe G]] |
| - | [[Category: Rechlin, C]] | + | [[Category: Rechlin C]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Tim barrel]]
| + | |
| Structural highlights
Function
ALDR_HUMAN Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
Publication Abstract from PubMed
Insights into the thermodynamic and kinetic signature of the transient opening of a protein-binding pocket resulting from accommodation of suitable substituents attached to a given parent ligand scaffold are presented. As a target, we selected human aldose reductase, an enzyme involved in the development of late-stage diabetic complications. To recognize a large scope of substrate molecules, this reductase opens a transient specificity pocket. The pocket-opening step was studied by X-ray crystallography, microcalorimetry, and surface plasmon resonance using a narrow series of 2-carbamoyl-phenoxy-acetic acid derivatives. Molecular dynamics simulations suggest that pocket opening occurs only once an appropriate substituent is attached to the parent scaffold. Transient pocket opening of the uncomplexed protein is hardly recorded. Hydration-site analysis suggests that up to five water molecules entering the opened pocket cannot stabilize this state. Sole substitution with a benzyl group stabilizes the opened state, and the energetic barrier for opening is estimated to be approximately 5 kJ/mol. Additional decoration of the pocket-opening benzyl substituent with a nitro group results in a huge enthalpy-driven potency increase; on the other hand, an isosteric carboxylic acid group reduces the potency 1000-fold, and binding occurs without pocket opening. We suggest a ligand induced-fit mechanism for the pocket-opening step, which, however, does not represent the rate-determining step in binding kinetics.
Price for Opening the Transient Specificity Pocket in Human Aldose Reductase upon Ligand Binding: Structural, Thermodynamic, Kinetic, and Computational Analysis.,Rechlin C, Scheer F, Terwesten F, Wulsdorf T, Pol E, Fridh V, Toth P, Diederich WE, Heine A, Klebe G ACS Chem Biol. 2017 May 19;12(5):1397-1415. doi: 10.1021/acschembio.7b00062. Epub, 2017 Apr 5. PMID:28287700[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rechlin C, Scheer F, Terwesten F, Wulsdorf T, Pol E, Fridh V, Toth P, Diederich WE, Heine A, Klebe G. Price for Opening the Transient Specificity Pocket in Human Aldose Reductase upon Ligand Binding: Structural, Thermodynamic, Kinetic, and Computational Analysis. ACS Chem Biol. 2017 May 19;12(5):1397-1415. doi: 10.1021/acschembio.7b00062. Epub, 2017 Apr 5. PMID:28287700 doi:http://dx.doi.org/10.1021/acschembio.7b00062
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