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Article: Crystal structure of the FK506 binding domain of Plasmodium falciparum FKBP35 in complex with FK506

TitleCrystal structure of the FK506 binding domain of Plasmodium falciparum FKBP35 in complex with FK506
Authors
Issue Date2008
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2008, v. 47 n. 22, p. 5951-5961 How to Cite?
AbstractThe emergence of multi-drug-resistant strains of Plasmodium parasites has prompted the search for alternative therapeutic strategies for combating malaria. One possible strategy is to exploit existing drugs as lead compounds. FK506 is currently used in the clinic for preventing transplant rejection. It binds to a α/β protein module of approximately 120 amino acids known as the FK506 binding domain (FKBD), which is found in various organisms, including human, yeast, and Plasmodium falciparum (PfFKBD). Antiparasitic effects of FK506 and its analogues devoid of immunosuppressive activities have been demonstrated. We report here the crystallographic structure at 2.35 Å resolution of PfFKBD complexed with FK506. Compared to the human FKBP12-FK506 complex reported earlier, the structure reveals structural differences in the β5-β6 segment that lines the FK506 binding site. The presence in PfFKBD of Cys-106 and Ser-109 (substituting for His-87 and Ile-90, respectively, in human FKBP12), which are 4-5 Å from the nearest atom of the FK506 compound, suggests possible routes for the rational design of analogues of FK506 with specific antiparasitic activity. Upon ligand binding, several conformational changes occur in PfFKBD, including aromatic residues that shape the FK506 binding pocket as shown by NMR studies. A microarray analysis suggests that FK506 and cyclosporine A (CsA) might inhibit parasite development by interfering with the same signaling pathways. © 2008 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/171765
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorKotaka, Men_US
dc.contributor.authorYe, Hen_US
dc.contributor.authorAlag, Ren_US
dc.contributor.authorHu, Gen_US
dc.contributor.authorBozdech, Zen_US
dc.contributor.authorPreiser, PRen_US
dc.contributor.authorHo, SYen_US
dc.contributor.authorLescar, Jen_US
dc.date.accessioned2012-10-30T06:16:53Z-
dc.date.available2012-10-30T06:16:53Z-
dc.date.issued2008en_US
dc.identifier.citationBiochemistry, 2008, v. 47 n. 22, p. 5951-5961en_US
dc.identifier.issn0006-2960en_US
dc.identifier.urihttp://hdl.handle.net/10722/171765-
dc.description.abstractThe emergence of multi-drug-resistant strains of Plasmodium parasites has prompted the search for alternative therapeutic strategies for combating malaria. One possible strategy is to exploit existing drugs as lead compounds. FK506 is currently used in the clinic for preventing transplant rejection. It binds to a α/β protein module of approximately 120 amino acids known as the FK506 binding domain (FKBD), which is found in various organisms, including human, yeast, and Plasmodium falciparum (PfFKBD). Antiparasitic effects of FK506 and its analogues devoid of immunosuppressive activities have been demonstrated. We report here the crystallographic structure at 2.35 Å resolution of PfFKBD complexed with FK506. Compared to the human FKBP12-FK506 complex reported earlier, the structure reveals structural differences in the β5-β6 segment that lines the FK506 binding site. The presence in PfFKBD of Cys-106 and Ser-109 (substituting for His-87 and Ile-90, respectively, in human FKBP12), which are 4-5 Å from the nearest atom of the FK506 compound, suggests possible routes for the rational design of analogues of FK506 with specific antiparasitic activity. Upon ligand binding, several conformational changes occur in PfFKBD, including aromatic residues that shape the FK506 binding pocket as shown by NMR studies. A microarray analysis suggests that FK506 and cyclosporine A (CsA) might inhibit parasite development by interfering with the same signaling pathways. © 2008 American Chemical Society.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_US
dc.relation.ispartofBiochemistryen_US
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntimalarials - Chemistry - Metabolismen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshCalcineurin - Chemistryen_US
dc.subject.meshCrystallography, X-Rayen_US
dc.subject.meshHumansen_US
dc.subject.meshLigandsen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshPlasmodium Falciparumen_US
dc.subject.meshProtein Structure, Tertiaryen_US
dc.subject.meshProtozoan Proteins - Chemistry - Metabolismen_US
dc.subject.meshTacrolimus - Chemistry - Metabolismen_US
dc.subject.meshTacrolimus Binding Proteins - Chemistry - Metabolismen_US
dc.titleCrystal structure of the FK506 binding domain of Plasmodium falciparum FKBP35 in complex with FK506en_US
dc.typeArticleen_US
dc.identifier.emailKotaka, M:masayo@hku.hken_US
dc.identifier.authorityKotaka, M=rp00293en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1021/bi800004uen_US
dc.identifier.pmid18465874-
dc.identifier.scopuseid_2-s2.0-44449107714en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-44449107714&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume47en_US
dc.identifier.issue22en_US
dc.identifier.spage5951en_US
dc.identifier.epage5961en_US
dc.identifier.isiWOS:000256256200007-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridKotaka, M=6604073578en_US
dc.identifier.scopusauthoridYe, H=54787149800en_US
dc.identifier.scopusauthoridAlag, R=24333925600en_US
dc.identifier.scopusauthoridHu, G=23034841400en_US
dc.identifier.scopusauthoridBozdech, Z=7007157687en_US
dc.identifier.scopusauthoridPreiser, PR=7004076971en_US
dc.identifier.scopusauthoridHo, SY=8957382100en_US
dc.identifier.scopusauthoridLescar, J=6603844493en_US
dc.identifier.citeulike2774439-

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