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          Institute: MPI für medizinische Forschung     Collection: Jahbruch 2014_archival     Display Documents



ID: 681448.0, MPI für medizinische Forschung / Jahbruch 2014_archival
Crystal structure of the Plasmodium falciparum thioredoxin reductase−thioredoxin complex
Translation of Title:Crystal structure of the Plasmodium falciparum thioredoxin reductase−thioredoxin complex
Authors:Fritz−Wolf, Karin; Jortzik, Esther; Stumpf, Michaela; Preuss, Janina; Iozef, Rimma; Rahlfs, Stefan; Becker, Katja
Language:English
Date of Publication (YYYY-MM-DD):2013-09-23
Title of Journal:Journal of Molecular Biology
Journal Abbrev.:J. Mol. Biol.
Volume:425
Issue / Number:18
Start Page:3446
End Page:3460
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Over the last decades, malaria parasites have been rapidly developing resistance against antimalarial drugs, which underlines the need for novel drug targets. Thioredoxin reductase (TrxR) is crucially involved in redox homeostasis and essential for Plasmodium falciparum. Here, we report the first crystal structure of P. falciparum TrxR bound to its substrate thioredoxin 1. Upon complex formation, the flexible C−terminal arm and an insertion loop of PfTrxR are rearranged, suggesting that the C−terminal arm changes its conformation during catalysis similar to human TrxR. Striking differences between P. falciparum and human TrxR are a Plasmodium−specific insertion and the conformation of the C−terminal arm, which lead to considerable differences in thioredoxin binding and disulfide reduction. Moreover, we functionally analyzed amino acid residues involved in substrate binding and in the architecture of the intersubunit cavity, which is a known binding site for disulfide reductase inhibitors. Cell biological experiments indicate that P. falciparum TrxR is indeed targeted in the parasite by specific inhibitors with antimalarial activity. Differences between P. falciparum and human TrxR and details on substrate reduction and inhibitor binding provide the first solid basis for structure−based drug development and lead optimization
Free Keywords:disulfide reductase;
protein complex crystallization;
malaria;
drug target;
redox system
External Publication Status:published
Document Type:Article
Communicated by:wkaiser
Affiliations:MPI für medizinische Forschung/Abteilung Biophysik
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen
Identifiers:LOCALID:7922
URI:http%3A%2F%2Fwww.sciencedirect.com%2Fscience%2Fart...
URI:http%3A%2F%2Fwww.sciencedirect.com%2Fscience%2Fart...
URI:http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpubmed%2F23845...
DOI:10.1016%2Fj.jmb.2013.06.037
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