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|1us0, resolution 0.66Å ()|
|Related:||1abn, 1ads, 1az1, 1az2, 1ef3, 1el3, 1iei, 1mar, 2acq, 2acr, 2acs, 2acu|
HUMAN ALDOSE REDUCTASE IN COMPLEX WITH NADP+ AND THE INHIBITOR IDD594 AT 0.66 ANGSTROM
The first subatomic resolution structure of a 36 kDa protein [aldose reductase (AR)] is presented. AR was cocrystallized at pH 5.0 with its cofactor NADP+ and inhibitor IDD 594, a therapeutic candidate for the treatment of diabetic complications. X-ray diffraction data were collected up to 0.62 A resolution and treated up to 0.66 A resolution. Anisotropic refinement followed by a blocked matrix inversion produced low standard deviations (<0.005 A). The model was very well ordered overall (CA atoms' mean B factor is 5.5 A2). The model and the electron-density maps revealed fine features, such as H-atoms, bond densities, and significant deviations from standard stereochemistry. Other features, such as networks of hydrogen bonds (H bonds), a large number of multiple conformations, and solvent structure were also better defined. Most of the atoms in the active site region were extremely well ordered (mean B approximately 3 A2), leading to the identification of the protonation states of the residues involved in catalysis. The electrostatic interactions of the inhibitor's charged carboxylate head with the catalytic residues and the charged coenzyme NADP+ explained the inhibitor's noncompetitive character. Furthermore, a short contact involving the IDD 594 bromine atom explained the selectivity profile of the inhibitor, important feature to avoid toxic effects. The presented structure and the details revealed are instrumental for better understanding of the inhibition mechanism of AR by IDD 594, and hence, for the rational drug design of future inhibitors. This work demonstrates the capabilities of subatomic resolution experiments and stimulates further developments of methods allowing the use of the full potential of these experiments.
Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A., Howard EI, Sanishvili R, Cachau RE, Mitschler A, Chevrier B, Barth P, Lamour V, Van Zandt M, Sibley E, Bon C, Moras D, Schneider TR, Joachimiak A, Podjarny A, Proteins. 2004 Jun 1;55(4):792-804. PMID:15146478
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Howard EI, Sanishvili R, Cachau RE, Mitschler A, Chevrier B, Barth P, Lamour V, Van Zandt M, Sibley E, Bon C, Moras D, Schneider TR, Joachimiak A, Podjarny A. Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A. Proteins. 2004 Jun 1;55(4):792-804. PMID:15146478 doi:10.1002/prot.20015
- Van Zandt MC, Sibley EO, McCann EE, Combs KJ, Flam B, Sawicki DR, Sabetta A, Carrington A, Sredy J, Howard E, Mitschler A, Podjarny AD. Design and synthesis of highly potent and selective (2-arylcarbamoyl-phenoxy)-acetic acid inhibitors of aldose reductase for treatment of chronic diabetic complications. Bioorg Med Chem. 2004 Nov 1;12(21):5661-75. PMID:15465344 doi:10.1016/j.bmc.2004.07.062
- Chen X, Weber I, Harrison RW. Hydration water and bulk water in proteins have distinct properties in radial distributions calculated from 105 atomic resolution crystal structures. J Phys Chem B. 2008 Sep 25;112(38):12073-80. Epub 2008 Aug 28. PMID:18754631 doi:10.1021/jp802795a