PDBsum entry 1u7t

Oxidoreductase

PDB id: 1u7t

Contents

Protein chains

255 a.a. *

Ligands

TDT ×3

NAD

Waters ×282

* Residue conservation analysis

PDB id:

1u7t

Name:

Oxidoreductase

Title:

Crystal structure of abad/hsd10 with a bound inhibitor

Structure:

3-hydroxyacyl-coa dehydrogenase type ii. Chain: a, b, c, d. Synonym: type ii hadh, endoplasmic reticulum-associated amyloid beta- peptide binding protein, short-chain type dehydrogenase/reductase xh98g2, amyloid beta-peptide-binding alcohol dehydrogenase, abad. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hadh2, erab, xh98g2, schad. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.00Å R-factor: 0.215 R-free: 0.263

Authors:

C.R.Kissinger,P.A.Rejto,L.A.Pelletier,R.E.Showalter,J.E.Villafranca

Key ref:

C.R.Kissinger et al. (2004). Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics. J Mol Biol, 342, 943-952. PubMed id: 15342248 DOI: 10.1016/j.jmb.2004.07.071

Date:

04-Aug-04 Release date: 05-Oct-04

Protein chains

Q99714  (HCD2_HUMAN) -  3-hydroxyacyl-CoA dehydrogenase type-2 from Homo sapiens

Seq: 261 a.a.

Struc: 255 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: E.C.1.1.1.159 - 7alpha-hydroxysteroid dehydrogenase.
• Reaction: cholate + NAD⁺ = 3alpha,12alpha-dihydroxy-7-oxo-5beta-cholanate + NADH + H⁺

cholate + NAD(+) (Bound ligand (Het Group name = TDT) matches with 62.86% similarity) = 3alpha,12alpha-dihydroxy-7-oxo-5beta-cholanate + NADH + H(+)

• Enzyme class 3: E.C.1.1.1.178 - 3-hydroxy-2-methylbutyryl-CoA dehydrogenase.
• Reaction: (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA + NAD⁺ = 2-methyl-3-oxobutanoyl- CoA + NADH + H⁺

(2S,3S)-3-hydroxy-2-methylbutanoyl-CoA (Bound ligand (Het Group name = NAD) matches with 50.00% similarity) + NAD(+) (Bound ligand (Het Group name = TDT) matches with 62.86% similarity) = 2-methyl-3-oxobutanoyl- CoA + NADH + H(+)

• Enzyme class 4: E.C.1.1.1.239 - 3alpha-(17beta)-hydroxysteroid dehydrogenase (NAD(+)).
• Reaction: testosterone + NAD⁺ = androst-4-ene-3,17-dione + NADH + H⁺

testosterone (Bound ligand (Het Group name = TDT) matches with 62.86% similarity) + NAD(+) = androst-4-ene-3,17-dione + NADH + H(+)

• Enzyme class 5: E.C.1.1.1.35 - 3-hydroxyacyl-CoA dehydrogenase.
• Reaction: a (3S)-3-hydroxyacyl-CoA + NAD⁺ = a 3-oxoacyl-CoA + NADH + H⁺

(3S)-3-hydroxyacyl-CoA (Bound ligand (Het Group name = NAD) matches with 50.77% similarity) + NAD(+) (Bound ligand (Het Group name = TDT) matches with 62.86% similarity) = 3-oxoacyl-CoA + NADH + H(+)

• Enzyme class 6: E.C.1.1.1.53 - 3alpha(or 20beta)-hydroxysteroid dehydrogenase.
• Reaction: androstan-3alpha,17beta-diol + NAD⁺ = 17beta-hydroxyandrostanone + NADH + H⁺

androstan-3alpha,17beta-diol + NAD(+) (Bound ligand (Het Group name = TDT) matches with 62.86% similarity) = 17beta-hydroxyandrostanone + NADH + H(+)

• Enzyme class 7: E.C.1.1.1.62 - 17beta-estradiol 17-dehydrogenase.
• Reaction:
  1. 17beta-estradiol + NAD⁺ = estrone + NADH + H⁺
  2. 17beta-estradiol + NADP⁺ = estrone + NADPH + H⁺

17beta-estradiol + NAD(+) (Bound ligand (Het Group name = TDT) matches with 62.86% similarity) = estrone + NADH + H(+)

17beta-estradiol + NADP(+) (Bound ligand (Het Group name = TDT) matches with 59.46% similarity) = estrone + 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.2004.07.071

J Mol Biol 342:943-952 (2004)

PubMed id: 15342248

Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics.

C.R.Kissinger, P.A.Rejto, L.A.Pelletier, J.A.Thomson, R.E.Showalter, M.A.Abreo, C.S.Agree, S.Margosiak, J.J.Meng, R.M.Aust, D.Vanderpool, B.Li, A.Tempczyk-Russell, J.E.Villafranca.

ABSTRACT

The enzyme 17beta-hydroxysteroid dehydrogenase type 10 (HSD10), also known as amyloid beta-peptide-binding alcohol dehydrogenase (ABAD), has been implicated in the development of Alzheimer's disease. This protein, a member of the short-chain dehydrogenase/reductase family of enzymes, has been shown to bind beta-amyloid and to participate in beta-amyloid neurotoxicity. We have determined the crystal structure of human ABAD/HSD10 complexed with NAD(+) and an inhibitory small molecule. The inhibitor occupies the substrate-binding site and forms a covalent adduct with the NAD(+) cofactor. The crystal structure provides a basis for the design of potent, highly specific ABAD/HSD10 inhibitors with potential application in the treatment of Alzheimer's disease.

Selected figure(s)

Figure 1.
Figure 1. Structure of the ABAD/HSD10 monomer. (a) Stereo C^a trace of ABAD/HSD10 monomer. Every tenth residue is numbered. The bound NAD-inhibitor adduct is shown. (b) Ribbon diagram of ABAD/HSD10 monomer, with the NAD-inhibitor adduct shown in ball-and-stick representation. The ribbon is white at the amino terminus and becomes darker blue moving toward the carboxy terminus. C^a positions of residues in the insertion regions of ABAD/HSD10 relative to other SDR enzymes (residues 102-107 and 141-146, see Figure 2) are shown as yellow spheres.

Figure 3.
Figure 3. Ribbon representation of the ABAD/HSD10 tetramer. The tetramer is viewed down one of three mutually perpendicular 2-fold axes. Individual monomers are shown in red, green, blue and yellow. The bound NAD^+ and NAD-inhibitor adduct molecules are shown in ball-and-stick representation.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2004, 342, 943-952) copyright 2004.

Figures were selected by the author.