The structure of human aldose reductase bound to the inhibitor IDD384

Calderone, V.; Chevrier, Bernard; Zandt, M. Van; Lamour, Valérie; Howard, Eduardo; Poterszman, Arnaud; Barth, Patrick; Mitschler, A.; Lu, Jiayi; Dvornik, D.; Klebe, G.; Kraemer, Oliver; Moorman, Allan R.; Moras, Dino; Podjarny, A.

doi:10.1107/s0907444900002341

Cited by 32 publications

(36 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The placement of the carboxylic group seems to further depend on the constitution of the attached side-chain, and the adopted binding mode of the ligand: as depicted in Figure 3, the carboxylate anchor of IDD384 (6, Figure 1), crystallized at pH 5, adopts a further conformation coordinating to Tyr48 and His110, whereas its sulfonyl group present in the attached side-chain places one of its oxygen atoms in a position well-suited to hydrogen bond to Trp111 N ε1 . 43 It actually coincides with the water position in the complex with 1.…”

Section: Resultsmentioning

confidence: 86%

Structural and Thermodynamic Study on Aldose Reductase: Nitro-substituted Inhibitors with Strong Enthalpic Binding Contribution

Steuber

Heine

Klebe

2007

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 86%

Structural and Thermodynamic Study on Aldose Reductase: Nitro-substituted Inhibitors with Strong Enthalpic Binding Contribution

Steuber

Heine

Klebe

2007

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

“…The most significant divergence in this group is the perpendicular position into the specificity pocket of tolrestat [19]. A nonequivalent binding was found for IDD384 [23] crystallised at pH 5. This inhibitor -longer than the previous ones -binds without any substantial protein conformational change and without opening the specificity pocket ( fig.…”

Section: Comparison With Other Published Carboxylate Inhibitorsmentioning

confidence: 82%

“…The same inhibitor has another carboxyl conformation when complexed (at pH 6.2) with pig AR [14]. [23]. As the pKa of IDD384 is 4.2, the inhibitor probably has a diferent protonation state in each complex (at pH 5 an important portion could be protonated).…”

Section: Comparison With Other Published Carboxylate Inhibitorsmentioning

confidence: 96%

Subatomic and atomic crystallographic studies of aldose reductase: implications for inhibitor binding

Podjarny

Cachau

Schneider

et al. 2004

Cellular and Molecular Life Sciences (CMLS)

View full text Add to dashboard Cite

The determination of several of aldose reductase-inhibitor complexes at subatomic resolution has revealed new structural details, including the specific interatomic contacts involved in inhibitor binding. In this article, we review the structures of the complexes of ALR2 with IDD 594 (resolution: 0.66 angstrom, IC50 (concentration of the inhibitor that produced half-maximal effect): 30 nM, space group: P2(1)), IDD 393 (resolution: 0.90 angstrom, IC50: 6 nM, space group: P1), fidarestat (resolution: 0.92 angstrom, IC50: 9 nM, space group: P2(1)) and minalrestat (resolution: 1.10 angstrom, IC50: 73 nM, space group: P1). The structures are compared and found to be highly reproductible within the same space group (root mean square (RMS) deviations: 0.15 approximately 0.3 angstrom). The mode of binding of the carboxylate inhibitors IDD 594 and IDD 393 is analysed. The binding of the carboxylate head can be accurately determined by the subatomic resolution structures, since both the protonation states and the positions of the atoms are very precisely known. The differences appear in the binding in the specificity pocket. The high-resolution structures explain the differences in IC50, which are confirmed both experimentally by mass spectrometry measures of VC50 and theoretically by free energy perturbation calculations. The binding of the cyclic imide inhibitors fidarestat and minalrestat is also described, focusing on the observation of a Cl(-) ion which binds simultaneously with fidarestat. The presence of this anion, binding also to the active site residue His110, leads to a mechanism in which the inhibitor can bind in a neutral state and then become charged inside the active site pocket. This mechanism can explain the excellent in vivo properties of cyclic imide inhibitors. In summary, the complete and detailed information supplied by the subatomic resolution structures can explain the differences in binding energy of the different inhibitors.

show abstract

“…Data were indexed and integrated using the MOSFLM program [12] and reduced using the SCALA program [13] from the CCP4 package [14]. The crystal structure of AKR4C7 (apoenzyme) was solved by molecular replacement using the MrBUMP program [15] from CCP4 and the structure of pig aldose reductase (PDB ID: 1EKO) as template [16]. The refined structure of the apo AKR4C7 was used as input in the AMORE program [17] to solve the crystal structure of the AKR4C7$NADP þ complex by molecular replacement.…”

Section: X-ray Diffraction Data Collection Processing and Structure mentioning

confidence: 99%

A comparative structural analysis reveals distinctive features of co-factor binding and substrate specificity in plant aldo-keto reductases

Giuseppe

Santos

Sousa

et al. 2016

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Plant aldo-keto reductases of the AKR4C subfamily play key roles during stress and are attractive targets for developing stress-tolerant crops. However, these AKR4Cs show little to no activity with previously-envisioned sugar substrates. We hypothesized a structural basis for the distinctive cofactor binding and substrate specificity of these plant enzymes. To test this, we solved the crystal structure of a novel AKR4C subfamily member, the AKR4C7 from maize, in the apo form and in complex with NADP(+). The binary complex revealed an intermediate state of cofactor binding that preceded closure of Loop B, and also indicated that conformational changes upon substrate binding are required to induce a catalytically-favorable conformation of the active-site pocket. Comparative structural analyses of homologues (AKR1B1, AKR4C8 and AKR4C9) showed that evolutionary redesign of plant AKR4Cs weakened interactions that stabilize the closed conformation of Loop B. This in turn decreased cofactor affinity and altered configuration of the substrate-binding site. We propose that these structural modifications contribute to impairment of sugar reductase activity in favor of other substrates in the plant AKR4C subgroup, and that catalysis involves a three-step process relevant to other AKRs.

show abstract

The structure of human aldose reductase bound to the inhibitor IDD384

Cited by 32 publications

References 11 publications

Structural and Thermodynamic Study on Aldose Reductase: Nitro-substituted Inhibitors with Strong Enthalpic Binding Contribution

Structural and Thermodynamic Study on Aldose Reductase: Nitro-substituted Inhibitors with Strong Enthalpic Binding Contribution

Subatomic and atomic crystallographic studies of aldose reductase: implications for inhibitor binding

A comparative structural analysis reveals distinctive features of co-factor binding and substrate specificity in plant aldo-keto reductases

Contact Info

Product

Resources

About