PDBsum entry 2feh

Oxidoreductase

PDB id: 2feh

Contents

Protein chains

333 a.a.

Ligands

DB0-DB0

DB0-DB0-DB0

Theoretical model

PDB id:

2feh

Name:

Oxidoreductase

Title:

Analysis of cgp-3466 docking to human placental gapdh

Structure:

Glyceraldehyde-3-phosphate dehydrogenase, liver. Chain: o, p, q, r. Synonym: gapdh. Engineered: yes

Source:

Homo sapiens. Human. Gene: gapd. Expressed in: escherichia coli.

Authors:

J.L.Jenkins,J.J.Tanner

Key ref:

J.L.Jenkins and J.J.Tanner (2006). High-resolution structure of human D-glyceraldehyde-3-phosphate dehydrogenase. Acta Crystallogr D Biol Crystallogr, 62, 290-301. PubMed id: 16510976 DOI: 10.1107/S0907444905042289

Date:

15-Dec-05 Release date: 07-Mar-06

Protein chains

P04406  (G3P_HUMAN) -  Glyceraldehyde-3-phosphate dehydrogenase

Seq: 335 a.a.

Struc: 333 a.a.

Enzyme reactions

• Enzyme class: E.C.1.2.1.12 - glyceraldehyde-3-phosphate dehydrogenase (phosphorylating).
• Pathway: Glyceraldehyde-3-phosphate Dehydrogenase (phosphorylating)
• Reaction: D-glyceraldehyde 3-phosphate + phosphate + NAD⁺ = (2R)-3-phospho- glyceroyl phosphate + NADH + H⁺

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

reference

DOI no: 10.1107/S0907444905042289

Acta Crystallogr D Biol Crystallogr 62:290-301 (2006)

PubMed id: 16510976

High-resolution structure of human D-glyceraldehyde-3-phosphate dehydrogenase.

J.L.Jenkins, J.J.Tanner.

ABSTRACT

GAPDH (D-glyceraldehyde-3-phosphate dehydrogenase) is a multifunctional protein that is a target for the design of antitrypanosomatid and anti-apoptosis drugs. Here, the first high-resolution (1.75 Angstroms) structure of a human GAPDH is reported. The structure shows that the intersubunit selectivity cleft that has been leveraged in the design of antitrypanosomatid compounds is closed in human GAPDH. Modeling of an anti-trypanosomatid GAPDH inhibitor in the human GAPDH active site provides insights into the basis for the observed selectivity of this class of inhibitor. Moreover, the high-resolution data reveal a new feature of the cleft: water-mediated intersubunit hydrogen bonds that assist closure of the cleft in the human enzyme. The structure is used in a computational ligand-docking study of the small-molecule compound CGP-3466, which inhibits apoptosis by preventing nuclear accumulation of GAPDH. Plausible binding sites are identified in the adenosine pocket of the NAD(+)-binding site and in a hydrophobic channel located in the center of the tetramer near the intersection of the three molecular twofold axes. The structure is also used to build a qualitative model of the complex between GAPDH and the E3 ubiquitin ligase Siah1. The model suggests that the convex surface near GAPDH Lys227 interacts with a large shallow groove of the Siah1 dimer. These results are discussed in the context of the recently discovered NO-S-nitrosylation-GAPDH-Siah1 apoptosis cascade.

Selected figure(s)

Figure 7.
Figure 7 Structures of HsGAPDH and Siah1 highlighting regions that are important for GAPDH-Siah1 association. (a) HsGAPDH tetramer viewed down the R axis. Subunits are colored as follows: O, yellow; P, red; Q, green; R, blue. Residues that are essential for complex formation with Siah1 are colored gray (residues 222-240) and atoms of Lys227 are drawn as spheres. (b) Homodimer of Siah1 from PDB entry 1k2f (Polekhina et al., 2002[Polekhina, G., House, C. M., Traficante, N., Mackay, J. P., Relaix, F., Sassoon, D. A., Parker, M. W. & Bowtell, D. D. (2002). Nature Struct. Biol. 9, 68-75.]). The two subunits of Siah1 are colored cyan and violet. Residues that are essential for interaction with GAPDH are colored yellow (residues 270-282).

Figure 8.
Figure 8 Qualitative model of the HsGAPDH-Siah1 complex. (a) Docked complex having the top score from PatchDock. A GAPDH subunit is shown in green and the Siah1 dimer is shown in cyan/violet. Only one subunit of the GAPDH dimer used for docking is shown for clarity. GAPDH residues 222-240 are colored gray. Siah1 residues 270-282 are colored yellow. GAPDH Lys227 and Siah1 Ser280 are drawn as spheres. (b) Model of a GAPDH tetramer interacting with four Siah1 dimers. This model was generated from the model in (a) using the symmetry of the GAPDH tetramer. The view is looking down the GAPDH R axis. GAPDH subunits are colored as follows: O, yellow; P, red; Q, green; R, blue. Siah1 dimers are colored cyan/violet and salmon/slate. (c) Surface representation of the model shown in (b).

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2006, 62, 290-301) copyright 2006.

Figures were selected by the author.