Document Detail

Structure of the complex between trypanosomal triosephosphate isomerase and N-hydroxy-4-phosphono-butanamide: binding at the active site despite an "open" flexible loop conformation.
MedLine Citation:
PMID:  1304889     Owner:  NLM     Status:  MEDLINE    
The structure of triosephosphate isomerase from Trypanosoma brucei complexed with the competitive inhibitor N-hydroxy-4-phosphono-butanamide was determined by X-ray crystallography to a resolution of 2.84 A. Full occupancy binding of the inhibitor is observed only at one of the active sites of the homodimeric enzyme where the flexible loop is locked in a completely open conformation by crystal contacts. There is evidence that the inhibitor also binds to the second active site of the enzyme, but with low occupancy. The hydroxamyl group of the inhibitor forms hydrogen bonds to the side chains of Asn 11, Lys 13, and His 95, whereas each of its three methylene units is involved in nonpolar interactions with the side chain of the flexible loop residue Ile 172. Interactions between the hydroxamyl and the catalytic base Glu 167 are absent. The binding of this phosphonate inhibitor exhibits three unusual features: (1) the flexible loop is open, in contrast with the binding mode observed in eight other complexes between triosephosphate isomerase and various phosphate and phosphonate compounds; (2) compared with these complexes the present structure reveals a 1.5-A shift of the anion-binding site; (3) this is the first phosphonate inhibitor that is not forced by the enzyme into an eclipsed conformation about the P-CH2 bond. The results are discussed with respect to an ongoing drug design project aimed at the selective inhibition of glycolytic enzymes of T. brucei.
C L Verlinde; C J Witmans; T Pijning; K H Kalk; W G Hol; M Callens; F R Opperdoes
Related Documents :
20607749 - Homology modeling and molecular dynamics simulation studies of human type 1 3β-hydroxys...
9485409 - Sequence and context dependence of ef-hand loop dynamics. an 15n relaxation study of a ...
22406319 - Off-target thiol alkylation by the nadph oxidase inhibitor 3-benzyl-7-(2-benzoxazolyl)t...
21650159 - Probing the allosteric mechanism in pyrrolysyl-trna synthetase using energy-weighted ne...
7779299 - Mathematical modelling of electrostatic fluctuations in subtilisin active site.
21645959 - A bifunctional allosteric site in the dimer interface of procaspase-3.
14737159 - Structure of the dengue virus envelope protein after membrane fusion.
9873499 - The structure-activity relationships of a series of suicide inhibitors of phospholipase...
20549499 - Stiffness of γ subunit of f(1)-atpase.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Protein science : a publication of the Protein Society     Volume:  1     ISSN:  0961-8368     ISO Abbreviation:  Protein Sci.     Publication Date:  1992 Dec 
Date Detail:
Created Date:  1993-07-15     Completed Date:  1993-07-15     Revised Date:  2010-09-07    
Medline Journal Info:
Nlm Unique ID:  9211750     Medline TA:  Protein Sci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1578-84     Citation Subset:  IM    
BIOSON Research Institute, University of Groningen, The Netherlands.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Amino Acid Sequence
Binding Sites
Macromolecular Substances
Models, Structural
Organophosphorus Compounds / metabolism*
Protein Binding
Protein Conformation*
Protein Structure, Secondary
Triose-Phosphate Isomerase / antagonists & inhibitors,  chemistry*,  metabolism*
Trypanosoma brucei brucei / enzymology*
X-Ray Diffraction
Reg. No./Substance:
0/Ligands; 0/Macromolecular Substances; 0/Organophosphorus Compounds; 146086-80-8/N-hydroxy-4-phosphonobutanamide; EC Isomerase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  A detailed consideration of a principal domain of vertebrate fibrinogen and its relatives.
Next Document:  Crystal structure of the Y52F/Y73F double mutant of phospholipase A2: increased hydrophobic interact...