Document Detail


Modeling the interaction between aldolase and the thrombospondin-related anonymous protein, a key connection of the malaria parasite invasion machinery.
MedLine Citation:
PMID:  17154157     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A complex molecular motor empowers substrate-dependent motility and host cell invasion in malaria parasites. The interaction between aldolase and the transmembrane adhesin thrombospondin-related anonymous protein (TRAP) transduces the motor force across the parasite surface. Here, we analyzed this interaction by using state-of-the-art flexible docking. Besides algorithms to account for induced fit in the side-chains of the Plasmodium falciparum aldolase (PfAldo) structure, we used additional in silico receptors modeled upon crystallographic structures of evolutionarily related aldolases to incorporate enzyme backbone flexibility, and to overcome structure inaccuracies due to the relatively low resolution (3.0 A) of the genuine PfAldo structure. Our results indicate that, in spite of multiple intermolecular contacts, only the six C-terminal residues of the TRAP cytoplasmic tail bind in an ordered manner to PfAldo. This portion of TRAP targets the PfAldo active site, with its n-1 Trp residue, which is essential for this interaction, buried within the PfAldo catalytic pocket. Docking of a TRAP peptide bearing a Trp to Ala mutation rendered the lower energy configurations either bound weakly outside the active site or not bound to PfAldo at all. The position of the bound TRAP peptide, and particularly the close proximity between the carbonyl of its n-2 Asp residue and the experimentally determined position of the phosphate-6 group of fructose 1,6-phosphate bound to mammalian aldolases, predicts an inhibitory effect of TRAP on catalysis. Enzymatic and TRAP-binding assays using mutant PfAldo molecules strongly support the overall structural model. These results might provide the initial framework for the identification of novel antiparasitic compounds.
Authors:
Carlos A Buscaglia; Wim G J Hol; Victor Nussenzweig; Timothy Cardozo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Proteins     Volume:  66     ISSN:  1097-0134     ISO Abbreviation:  Proteins     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-16     Completed Date:  2007-02-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8700181     Medline TA:  Proteins     Country:  United States    
Other Details:
Languages:  eng     Pagination:  528-37     Citation Subset:  IM    
Copyright Information:
2006 Wiley-Liss, Inc.
Affiliation:
Michael Heidelberg Division of Pathology of Infectious Diseases, Department of Pathology, New York University School of Medicine, New York, USA. buscac01@med.nyu.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
Crystallography, X-Ray
Fructose-Bisphosphate Aldolase / chemistry*,  genetics,  metabolism*
Humans
Kinetics
Ligands
Models, Molecular
Muscle, Skeletal / enzymology
Mutation
Protozoan Proteins / chemistry*,  metabolism*
Rabbits
Chemical
Reg. No./Substance:
0/Ligands; 0/Protozoan Proteins; 120300-02-9/thrombospondin-related adhesive protein, protozoan; EC 4.1.2.13/Fructose-Bisphosphate Aldolase

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


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