PDBsum entry: 1e6w

Dehydrogenase

PDB id: 1e6w

Contents

Protein chains

251 a.a. *

Ligands

NAD ×4

EST

Waters ×545

* Residue conservation analysis

PDB id:

1e6w

Name:

Dehydrogenase

Title:

Rat brain 3-hydroxyacyl-coa dehydrogenase binary complex with nadh and estradiol

Structure:

Short chain 3-hydroxyacyl-coa dehydrogenase. Chain: a, b, c, d. Synonym: 3-hydroxyacyl-coa dehydrogenase type ii, hadh ii, endoplasmic reticulum-associated amyloid beta-peptide binding protein. Engineered: yes

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Organ: brain. Organelle: mitochonria. Cellular_location: cytoplasm. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Biol. unit:

Tetramer (from PQS)

Resolution:

1.7Å R-factor: 0.184 R-free: 0.229

Authors:

J.A.Read,A.J.Powell,R.L.Brady

Key ref:

A.J.Powell et al. (2000). Recognition of structurally diverse substrates by type II 3-hydroxyacyl-CoA dehydrogenase (HADH II)/amyloid-beta binding alcohol dehydrogenase (ABAD). J Mol Biol, 303, 311-327. PubMed id: 11023795 DOI: 10.1006/jmbi.2000.4139

Date:

23-Aug-00 Release date: 25-May-01

Protein chains

O70351  (HCD2_RAT) -  3-hydroxyacyl-CoA dehydrogenase type-2

Seq: 261 a.a.

Struc: 251 a.a.

Enzyme reactions

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

(2S,3S)-3-hydroxy-2-methylbutanoyl-CoA + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = 2-methylacetoacetyl-CoA + NADH

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

(S)-3-hydroxyacyl-CoA + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = 3-oxoacyl-CoA + NADH

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

 Gene Ontology (GO) functional annotation 

• Cellular component: mitochondrion (3 terms)
• Biological process: metabolic process (6 terms)
• Biochemical function: nucleotide binding (11 terms)

reference

DOI no: 10.1006/jmbi.2000.4139

J Mol Biol 303:311-327 (2000)

PubMed id: 11023795

Recognition of structurally diverse substrates by type II 3-hydroxyacyl-CoA dehydrogenase (HADH II)/amyloid-beta binding alcohol dehydrogenase (ABAD).

A.J.Powell, J.A.Read, M.J.Banfield, F.Gunn-Moore, S.D.Yan, J.Lustbader, A.R.Stern, D.M.Stern, R.L.Brady.

ABSTRACT

Human type II hydroxyacyl-CoA dehydrogenase/amyloid-beta binding alcohol dehydrogenase (HADH II/ABAD) is an oxidoreductase whose salient features include broad substrate specificity, encompassing 3-hydroxyacyl-CoA derivatives, hydroxysteroids, alcohols and beta-hydroxybutyrate, and the capacity to bind amyloid-beta peptide, leading to propagation of amyloid-induced cell stress. In this study, we examine the structure and enzymatic activity of the homologous rat HADH II/ABAD enzyme. We report the crystal structure of rat HADH II/ABAD as a binary complex with its NADH cofactor to 2.0 A resolution, as a ternary complex with NAD(+) and 3-ketobutyrate (acetoacetate) to 1.4 A resolution, and as a ternary complex with NADH and 17 beta-estradiol to 1.7 A resolution. This first crystal structure of an HADH II confirms these enzymes are closely related to the short-chain hydroxysteroid dehydrogenases and differ substantially from the classic, type I 3-hydroxyacyl-CoA dehydrogenases. Binding of the ketobutyrate substrate is accompanied by closure of the active site specificity loop, whereas the steroid substrate does not appear to require closure for binding. Despite the different chemical nature of the two bound substrates, the presentation of chemical groups within the active site of each complex is remarkably similar, allowing a general mechanism for catalytic activity to be proposed. There is a characteristic extension to the active site that is likely to accommodate the CoA moiety of 3-hydroxyacyl-CoA substrates. Rat HADH II/ABAD also binds amyloid-beta (1-40) peptide with a K(D) of 21 nM, which is similar to the interaction exhibited between this peptide and human HADH II/ABAD. These studies provide the first structural insights into HADH II/ABAD interaction with its substrates, and indicate the relevance of the rodent enzyme and associated rodent models for analysis of HADH II/ABAD's physiologic and pathophysiologic properties.

Selected figure(s)

Figure 4.
Figure 4. Co-factor binding and catalytic mechanism of rHADH II/ABAD. (a) Schematic diagram showing inter- actions between NADH and rHADH II/ABAD. (b) Schematic diagram showing the proposed reaction mechanism of rHADH II/ABAD, based on structural similarity to other SDR enzymes and mechanism previously proposed for human 17b-hydroxysteroid dehydrogenase by Breton et al. (1996). The numbers adjacent to the hydrogen bonds (bro- ken lines) are the distances in angstroms measured between these groups in the respective crystal structures.

Figure 6.
Figure 6. Binding of CoA substrates to rHADH II. The Figure shows a model of the expected conformation of a bound acetoacetyl-CoA substrate. The C a trace of a single subunit of rHADH II/ABAD is shown in pale blue, with the co-factor in purple, acetoacetate group (from the crystal structure of the 3-ketobutyrate com- plex) in red, and the thioester-linked coenzyme A group in green. The two phosphate groups of the CoA moiety are labelled PA and PN, and adjacent conserved, posi- tively charged amino acid residues are also shown and labelled.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 303, 311-327) copyright 2000.

Figures were selected by an automated process.