Targeting a dynamic protein-protein interaction: fragment screening against the malaria myosin A motor complex.
ChemMedChem
; 10(1): 134-43, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-25367834
ABSTRACT
Motility is a vital feature of the complex life cycle of Plasmodium falciparum, the apicomplexan parasite that causes human malaria. Processes such as host cell invasion are thought to be powered by a conserved actomyosin motor (containing myosinâ
A or myoA), correct localization of which is dependent on a tight interaction with myosinâ
A tail domain interacting protein (MTIP) at the inner membrane of the parasite. Although disruption of this protein-protein interaction represents an attractive means to investigate the putative roles of myoA-based motility and to inhibit the parasitic life cycle, no small molecules have been identified that bind to MTIP. Furthermore, it has not been possible to obtain a crystal structure of the free protein, which is highly dynamic and unstable in the absence of its natural myoA tail partner. Herein we report the de novo identification of the first molecules that bind to and stabilize MTIP via a fragment-based, integrated biophysical approach and structural investigations to examine the binding modes of hit compounds. The challenges of targeting such a dynamic system with traditional fragment screening workflows are addressed throughout.
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Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Proteínas de Protozoários
/
Miosina não Muscular Tipo IIA
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article