4ys1 | pdb_00004ys1

Human Aldose Reductase complexed with a ligand with an IDD structure (2) at 1.07 A.

spinqualitylabelsall models 4ys1, resolution 1.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ys1 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4G7, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aldose reductase 3D structures

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