PDBsum entry 1i32

Oxidoreductase

PDB id: 1i32

Contents

Protein chains

(+ 0 more) 358 a.a. *

Ligands

NMD ×6

Waters ×657

* Residue conservation analysis

PDB id:

1i32

Name:

Oxidoreductase

Title:

Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase in complex with inhibitors

Structure:

Glyceraldehyde 3-phosphate dehydrogenase. Chain: a, b, c, d, e, f. Synonym: gapdh. Engineered: yes

Source:

Leishmania mexicana. Organism_taxid: 5665. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.60Å R-factor: 0.205 R-free: 0.256

Authors:

S.Suresh,J.C.Bressi,K.J.Kennedy,C.L.M.J.Verlinde,M.H.Gelb,W.G.J.Hol

Key ref:

S.Suresh et al. (2001). Conformational changes in Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase induced by designed inhibitors. J Mol Biol, 309, 423-435. PubMed id: 11371162 DOI: 10.1006/jmbi.2001.4588

Date:

12-Feb-01 Release date: 03-Oct-01

Protein chains

Q27890  (G3PG_LEIME) -  Glyceraldehyde-3-phosphate dehydrogenase, glycosomal from Leishmania mexicana

Seq: 361 a.a.

Struc: 358 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: 10.1006/jmbi.2001.4588

J Mol Biol 309:423-435 (2001)

PubMed id: 11371162

Conformational changes in Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase induced by designed inhibitors.

S.Suresh, J.C.Bressi, K.J.Kennedy, C.L.Verlinde, M.H.Gelb, W.G.Hol.

ABSTRACT

The glycolytic enzymes of trypanosomes are attractive drug targets, since the blood-stream form of Trypanosoma brucei lacks a functional citric acid cycle and is dependent solely on glycolysis for its energy requirements. Glyceraldehyde-3-phosphate dehydrogenases (GAPDH) from the pathogenic trypanosomatids T. brucei, Trypanosoma cruzi and Leishmania mexicana are quite similar to each other, and yet have sufficient structural differences compared to the human enzyme to enable the structure-based design of compounds that selectively inhibit all three trypanosomatid enzymes but not the human homologue.Adenosine analogs with substitutions on N-6 of the adenine ring and on the 2' position of the ribose moiety were designed, synthesized and tested for inhibition. Two crystal structures of L. mexicana glyceraldehyde-3-phosphate dehydrogenase in complex with high-affinity inhibitors that also block parasite growth were solved at a resolution of 2.6 A and 3.0 A. The complexes crystallized in the same crystal form, with one and a half tetramers in the crystallographic asymmetric unit. There is clear electron density for the inhibitor in all six copies of the binding site in each of the two structures. The L. mexicana GAPDH subunit exhibits substantial structural plasticity upon binding the inhibitor. Movements of the protein backbone, in response to inhibitor binding, enlarge a cavity at the binding site to accommodate the inhibitor in a classic example of induced fit. The extensive hydrophobic interactions between the protein and the two substituents on the adenine scaffold of the inhibitor provide a plausible explanation for the high affinity of these inhibitors for trypanosomatid GAPDHs.

Selected figure(s)

Figure 2.
Figure 2. (a) Model-unbiased 6-fold averaged 2F o - F c map of NMDBA bound to L. mexicana GAPDH at 2.6 A Ê con- toured at 0.82s to within 2.0 A Ê of NMDBA atoms. The map was calculated after refining the six protein monomers in the asymmetric unit and prior to modeling in the bound inhibitor (NMDBA, gold C atoms). In (a)-(d) residues in green and violet are from adjacent monomers of the biological tetramer. (b) Model-unbiased sixfold averaged 2F o - F c map of TNDBA bound to L. mexicana GAPDH at 3.0 A Ê , contoured at 0.82s to within 2.0 A Ê of TNDBA atoms. (a) and (b) were made with Bobscript. 41 (c) Superposition of the six copies of the bound inhibitor NMDBA (gold C atoms), in the crystal structure in complex with L. mexicana GAPDH. The 358 C a atoms of each monomer were used in the superposition. (d) Superposition of the crystal structures of L. mexicana GAPDH in complex with NMDBA (gold) and the structure in complex with TNDBA (grey). (c) and (d) Created with MOLSCRIPT 38 and Raster3D. 39,40

Figure 3.
Figure 3. (a) Schematic drawn by LIGPLOT 42 showing interactions of NMDBA with L. mexicana GAPDH. (b) Sche- matic drawn by LIGPLOT 42 showing interactions of TNDBA with L. mexicana GAPDH.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2001, 309, 423-435) copyright 2001.

Figures were selected by an automated process.