PDBsum entry 1us0

Oxidoreductase

PDB id: 1us0

Contents

Protein chain

314 a.a. *

Ligands

NDP

LDT

CIT ×2

Waters ×613

* Residue conservation analysis

PDB id:

1us0

Name:

Oxidoreductase

Title:

Human aldose reductase in complex with NADP+ and the inhibitor idd594 at 0.66 angstrom

Structure:

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

Source:

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

Resolution:

0.66Å R-factor: 0.094 R-free: 0.103

Authors:

E.I.Howard,R.Sanishvili,R.E.Cachau,A.Mitschler,B.Chevrier,P.Barth, V.Lamour,M.Van Zandt,E.Sibley,C.Bon,D.Moras,T.R.Schneider, A.Joachimiak,A.Podjarny

Key ref:

E.I.Howard et al. (2004). Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A. Proteins, 55, 792-804. PubMed id: 15146478 DOI: 10.1002/prot.20015

Date:

16-Nov-03 Release date: 07-May-04

Protein chain

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

Seq: 316 a.a.

Struc: 314 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 = NDP) matches with 91.67% similarity) = aldose + NADH + H(+)

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

glycerol + NADP(+) (Bound ligand (Het Group name = NDP) 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 = NDP) 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: 10.1002/prot.20015

Proteins 55:792-804 (2004)

PubMed id: 15146478

Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A.

E.I.Howard, R.Sanishvili, R.E.Cachau, A.Mitschler, B.Chevrier, P.Barth, V.Lamour, M.Van Zandt, E.Sibley, C.Bon, D.Moras, T.R.Schneider, A.Joachimiak, A.Podjarny.

ABSTRACT

The first subatomic resolution structure of a 36 kDa protein [aldose reductase 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.

Selected figure(s)

Figure 1.
Figure 1. Contacts of IDD 594 with AR and NADP^+. (a) 3D view of inhibitor contacts. View of the inhibitor-binding site down the barrel axis with the semitransparent representation of AR surface. The active site cleft (marked A), is occupied by the inhibitor (stick only; color code: C = gray, N = blue, O = red, F = pink, S = orange, Br = green) and surrounded by the catalytic residues His 110, Tyr 48, and the coenzyme NADP^+. The residues within 3.9 Å and NADP^+ are shown (balls and sticks). The specificity pocket between Leu 300, Phe 122, and Trp 111 (marked S) is occupied by the brominated aromatic ring of the inhibitor. (b) Scheme of IDD 594 and its contacts. Red dashed lines show contacts between 3.5 and 3.0 Å, and blue dashed lines show contacts <3.0 Å. The exact values are given in Table IV.

Figure 5.
Figure 5. Model of residues Cys 44 and Ala 45 superimposed with A-weighted Fo-Fc map with omitted hydrogen atoms (a), contoured magenta at at 0.25 e/Å^3 (2.5 ) showing the position of the hydrogen atoms and the bond densities. Model of residues Ser 76 and Lys 77(b), viewed down the C N peptide bond showing the angle of -167.3° stabilized by an H-bond.

The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2004, 55, 792-804) copyright 2004.

Figures were selected by an automated process.