PDBsum entry 2nvd

Oxidoreductase

PDB id: 2nvd

Contents

Protein chain

315 a.a. *

Ligands

NAP

ITB ×3

Waters ×214

* Residue conservation analysis

PDB id:

2nvd

Name:

Oxidoreductase

Title:

Human aldose reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (2)

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: halr2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.55Å R-factor: 0.192 R-free: 0.245

Authors:

H.Steuber,A.Heine,G.Klebe

Key ref:

H.Steuber et al. (2007). Evidence for a novel binding site conformer of aldose reductase in ligand-bound state. J Mol Biol, 369, 186-197. PubMed id: 17418233 DOI: 10.1016/j.jmb.2007.03.021

Date:

12-Nov-06 Release date: 24-Apr-07

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 1 residue position (black cross)

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 (Bound ligand (Het Group name = ITB) matches with 41.94% similarity) + 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.2007.03.021

J Mol Biol 369:186-197 (2007)

PubMed id: 17418233

Evidence for a novel binding site conformer of aldose reductase in ligand-bound state.

H.Steuber, M.Zentgraf, C.La Motta, S.Sartini, A.Heine, G.Klebe.

ABSTRACT

Human aldose reductase (ALR2) has evolved as a promising therapeutic target for the treatment of diabetic long-term complications. The binding site of this enzyme possesses two main subpockets: the catalytic anion-binding site and the hydrophobic specificity pocket. The latter can be observed in the open or closed state, depending on the bound ligand. Thus, it exhibits a pronounced capability for induced-fit adaptations, whereas the catalytic pocket exhibits rigid properties throughout all known crystal structures. Here, we determined two ALR2 crystal structures at 1.55 and 1.65 A resolution, each complexed with an inhibitor of the recently described naphtho[1,2-d]isothiazole acetic acid series. In contrast to the original design hypothesis based on the binding mode of tolrestat (1), both inhibitors leave the specificity pocket in the closed state. Unexpectedly, the more potent ligand (2) extends the catalytic pocket by opening a novel subpocket. Access to this novel subpocket is mainly attributed to the rotation of an indole moiety of Trp 20 by about 35 degrees . The newly formed subpocket provides accommodation of the naphthyl portion of the ligand. The second inhibitor, 3, differs from 2 only by an extended glycolic ester functionality added to one of its carboxylic groups. However, despite this slight structural modification, the binding mode of 3 differs dramatically from that of the first inhibitor, but provokes less pronounced induced-fit adaptations of the binding cavity. Thus, a novel binding site conformation has been identified in a region where previous complex structures suggested only low adaptability of the binding pocket. Furthermore, the two ligand complexes represent an impressive example of how the slight change of a chemically extended side-chain at a given ligand scaffold can result in a dramatically altered binding mode. In addition, our study emphasizes the importance of crystal structure analysis for the translation of affinity data into structure-activity relationships.

Selected figure(s)

Figure 1.
Figure 1. Chemical formulae of tolrestat (1), two members of the naphtho[1,2-d]isothiazole acetic acid series (2) and (3), sorbinil (4), and IDD 594 (5).

Figure 2.
Figure 2. Three parent binding pocket conformations of ALR2 observed in complexes with sorbinil, tolrestat, and IDD 594 (shown in light blue). Key interactions are shown as red dotted lines and waters as red spheres. (a) Binding mode of sorbinil with the specificity pocket in the closed state; the gating residues Trp 111 and Leu 300 mutually form van der Waals contacts. (b) In the ALR2–1 complex (tolrestat), Leu 300 adopts a kinked conformation and thereby opens the specificity pocket. (c) Binding geometry of 5 (IDD 594) with the enzyme; here, the halogen-substituted aromatic moiety intercalates into the space created between Trp 111 and Leu 300.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 369, 186-197) copyright 2007.

Figures were selected by an automated process.