PDBsum entry 2pdp

Oxidoreductase

PDB id: 2pdp

Contents

Protein chain

315 a.a. *

Ligands

NAP

393

Waters ×270

* Residue conservation analysis

PDB id:

2pdp

Name:

Oxidoreductase

Title:

Human aldose reductase mutant s302r complexed with idd 393.

Structure:

Aldose reductase. Chain: a. Synonym: ar, aldehyde reductase. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: alr2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.65Å R-factor: 0.171 R-free: 0.241

Authors:

H.Steuber,A.Heine,G.Klebe

Key ref:

H.Steuber et al. (2008). Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features. J Mol Biol, 379, 991-1016. PubMed id: 18495158 DOI: 10.1016/j.jmb.2008.03.063

Date:

01-Apr-07 Release date: 01-Apr-08

Protein chain

P15121  (ALDR_HUMAN) -  Aldo-keto reductase family 1 member B1 from Homo sapiens

Seq: 316 a.a.

Struc: 315 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.1.1.1.21 - aldose reductase.
• Reaction:
  1. an alditol + NAD⁺ = an aldose + NADH + H⁺
  2. an alditol + NADP⁺ = an aldose + NADPH + H⁺

alditol + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = aldose + NADH + H(+)

alditol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = aldose + NADPH + H(+)

• Enzyme class 2: E.C.1.1.1.300 - NADP-retinol dehydrogenase.
• Reaction: all-trans-retinol + NADP⁺ = all-trans-retinal + NADPH + H⁺

all-trans-retinol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = all-trans-retinal + NADPH + H(+)

• Enzyme class 3: E.C.1.1.1.372 - D/L-glyceraldehyde reductase.
• Reaction:
  1. glycerol + NADP⁺ = L-glyceraldehyde + NADPH + H⁺
  2. glycerol + NADP⁺ = D-glyceraldehyde + NADPH + H⁺

glycerol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = L-glyceraldehyde + NADPH + H(+)

glycerol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = D-glyceraldehyde + NADPH + H(+)

• Enzyme class 4: E.C.1.1.1.54 - allyl-alcohol dehydrogenase.
• Reaction: allyl alcohol + NADP⁺ = acrolein + NADPH + H⁺

allyl alcohol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = acrolein + NADPH + H(+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.jmb.2008.03.063

J Mol Biol 379:991-1016 (2008)

PubMed id: 18495158

Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.

H.Steuber, A.Heine, A.Podjarny, G.Klebe.

ABSTRACT

Inhibition of human aldose reductase (ALR2) evolved as a promising therapeutic concept to prevent late complications of diabetes. As well as appropriate affinity and bioavailability, putative inhibitors should possess a high level of selectivity for ALR2 over the related aldehyde reductase (ALR1). We investigated the selectivity-determining features by gradually mapping the residues deviating between the binding pockets of ALR1 and ALR2 into the ALR2 binding pocket. The resulting mutational constructs of ALR2 (eight point mutations and one double mutant) were probed for their influence towards ligand selectivity by X-ray structure analysis of the corresponding complexes and isothermal titration calorimetry (ITC). The binding properties of these mutants were evaluated using a ligand set of zopolrestat, a related uracil derivative, IDD388, IDD393, sorbinil, fidarestat and tolrestat. Our study revealed induced-fit adaptations within the mutated binding site as an essential prerequisite for ligand accommodation related to the selectivity discrimination of the ligands. However, our study also highlights the limits of the present understanding of protein-ligand interactions. Interestingly, binding site mutations not involved in any direct interaction to the ligands in various cases show significant effects towards their binding thermodynamics. Furthermore, our results suggest the binding site residues deviating between ALR1 and ALR2 influence ligand affinity in a complex interplay, presumably involving changes of dynamic properties and differences of the solvation/desolvation balance upon ligand binding.

Selected figure(s)

Figure 1.
Fig. 1. Comparative stereo representations of the related ALR1 (a) and ALR2 (b) inhibitor binding pockets.

Figure 2.
Fig. 2. Chemical formulae of the ALR2 inhibitors investigated in this study.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 379, 991-1016) copyright 2008.

Figures were selected by the author.