3mb9: Difference between revisions
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==Human Aldose Reductase mutant T113A complexed with Zopolrestat== | |||
<StructureSection load='3mb9' size='340' side='right'caption='[[3mb9]], [[Resolution|resolution]] 1.65Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mb9]] 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=3MB9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MB9 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=ZST:3,4-DIHYDRO-4-OXO-3-((5-TRIFLUOROMETHYL-2-BENZOTHIAZOLYL)METHYL)-1-PHTHALAZINE+ACETIC+ACID'>ZST</scene></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=3mb9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mb9 OCA], [https://pdbe.org/3mb9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mb9 RCSB], [https://www.ebi.ac.uk/pdbsum/3mb9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mb9 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
BACKGROUND: Flexibility is a common feature of proteins. For human aldose reductase, a variety of conformers have been observed in crystalline complexes with different inhibitors. METHODS: A study of crystal structures and isothermal titration calorimetry was performed on wild type and mutated aldose reductase. RESULTS AND CONCLUSIONS: Though the interaction to the mutated residue Thr113 does not directly alter the binding mode of zopolrestat to aldose reductase, a shift of its basic scaffold is induced which affects the interaction with a flexible loop and introduces disorder. With the related inhibitor IDD393, two distinct binding site conformations result in two different crystal forms: While a backbone flip of the same residues as for zopolrestat is present in both crystal forms, a considerable side-chain movement of a phenylalanine is observed for only one crystal form. In consequence, residual mobility of adjacent amino acids is increased and some crystal contacts are prevented which reinforces different crystal packing. The structure of a benzothiazepine reveals a protein conformer, where this phenylalanine is further relocated resulting in the same altered crystal packing. Differences in the thermodynamic signature recorded for the various complexes relate to the structural differences. GENERAL SIGNIFICANCE: Crystal structures are accepted as "gold standard" for the interpretation of protein geometry, however, they are only one possible structure and can be influenced by crystal packing. In reverse, ligand binding can affect protein conformation and determine crystal packing. The phenomenon of such "polymorphic forms" is well appreciated, however rarely understood at the molecular level. | |||
Ligand-induced fit affects binding modes and provokes changes in crystal packing of aldose reductase.,Koch C, Heine A, Klebe G Biochim Biophys Acta. 2011 Sep;1810(9):879-87. Epub 2011 Jun 13. PMID:21684320<ref>PMID:21684320</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3mb9" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Aldose | *[[Aldose reductase 3D structures|Aldose reductase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Heine A]] | ||
[[Category: | [[Category: Klebe G]] | ||
[[Category: | [[Category: Koch C]] | ||
Latest revision as of 13:41, 16 August 2023
Human Aldose Reductase mutant T113A complexed with ZopolrestatHuman Aldose Reductase mutant T113A complexed with Zopolrestat
Structural highlights
FunctionALDR_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 PubMedBACKGROUND: Flexibility is a common feature of proteins. For human aldose reductase, a variety of conformers have been observed in crystalline complexes with different inhibitors. METHODS: A study of crystal structures and isothermal titration calorimetry was performed on wild type and mutated aldose reductase. RESULTS AND CONCLUSIONS: Though the interaction to the mutated residue Thr113 does not directly alter the binding mode of zopolrestat to aldose reductase, a shift of its basic scaffold is induced which affects the interaction with a flexible loop and introduces disorder. With the related inhibitor IDD393, two distinct binding site conformations result in two different crystal forms: While a backbone flip of the same residues as for zopolrestat is present in both crystal forms, a considerable side-chain movement of a phenylalanine is observed for only one crystal form. In consequence, residual mobility of adjacent amino acids is increased and some crystal contacts are prevented which reinforces different crystal packing. The structure of a benzothiazepine reveals a protein conformer, where this phenylalanine is further relocated resulting in the same altered crystal packing. Differences in the thermodynamic signature recorded for the various complexes relate to the structural differences. GENERAL SIGNIFICANCE: Crystal structures are accepted as "gold standard" for the interpretation of protein geometry, however, they are only one possible structure and can be influenced by crystal packing. In reverse, ligand binding can affect protein conformation and determine crystal packing. The phenomenon of such "polymorphic forms" is well appreciated, however rarely understood at the molecular level. Ligand-induced fit affects binding modes and provokes changes in crystal packing of aldose reductase.,Koch C, Heine A, Klebe G Biochim Biophys Acta. 2011 Sep;1810(9):879-87. Epub 2011 Jun 13. PMID:21684320[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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