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Computational prediction of structure, substrate binding mode, mechanism, and rate for a malaria protease with a novel type of active site.
Uppsala University.ORCID iD: 0000-0002-9300-614X
2004 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 43, no 46, 14521-14528 p.Article in journal (Refereed) Published
Abstract [en]

The histo-aspartic protease (HAP) from the malaria parasite P. falciparum is one of several new promising targets for drug intervention. The enzyme possesses a novel type of active site, but its 3D structure and mechanism of action are still unknown. Here we use a combination of homology modeling, automated docking searches, and molecular dynamics/reaction free energy profile simulations to predict the enzyme structure, conformation of bound substrate, catalytic mechanism, and rate of the peptide cleavage reaction. We find that the computational tools are sufficiently reliable both for identifying substrate binding modes and for distinguishing between different possible reaction mechanisms. It is found that the favored pathway only involves direct participation by the catalytic aspartate, with the neighboring histidine providing critical stabilization (by a factor of approximately 10000) along the reaction. The calculated catalytic rate constant of about 0.1 s(-1) for a hexapeptide substrate derived from the alpha chain of human hemoglobin is in excellent agreement with experimental kinetic data for a similar peptide fragment.

Place, publisher, year, edition, pages
2004. Vol. 43, no 46, 14521-14528 p.
National Category
Biochemistry and Molecular Biology
Research subject
Chemistry, Biochemistry
Identifiers
URN: urn:nbn:se:lnu:diva-51104DOI: 10.1021/bi048252qPubMedID: 15544322OAI: oai:DiVA.org:lnu-51104DiVA: diva2:913265
Available from: 2016-03-21 Created: 2016-03-21 Last updated: 2016-03-21Bibliographically approved

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