Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum

doi:10.1074/jbc.M60377200

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	Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum
	Hogg, Tanis ; Nagarajan, Krishna ; Herzberg, Saskia ; Chen, Lili; Shen, Xu; Jiang, Hualiang; Wecke, Maria ; Blohmke, Christoph ; Hilgenfeld, Rolf ; Schmidt, Christian L.
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2006-09-01
卷号	281 期号:35 页码:25425-25437
ISSN号	0021-9258
DOI	10.1074/jbc.M60377200
文献子类	Article
英文摘要	Malaria is caused by protozoan erythrocytic parasites of the Plasmodium genus, with Plasmodium falciparum being the most dangerous and widespread disease-causing species. Falcipain-2 (FP-2) of P. falciparum is a papain-family (C1A) cysteine protease that plays an important role in the parasite life cycle by degrading erythrocyte proteins, most notably hemoglobin. Inhibition of FP-2 and its paralogues prevents parasite maturation, suggesting these proteins may be valuable targets for the design of novel antimalarial drugs, but lack of structural knowledge has impeded progress toward the rational discovery of potent, selective, and efficacious inhibitors. As a first step toward this goal, we present here the crystal structure of mature FP-2 at 3.1 angstrom resolution, revealing novel structural features of the FP-2 subfamily proteases including a dynamic beta-hairpin hemoglobin binding motif, a flexible N-terminal alpha-helical extension, and a unique active-site cleft. We also demonstrate by biochemical methods that mature FP-2 can proteolytically process its own precursor in trans at neutral to weakly alkaline pH, that the binding of hemoglobin to FP-2 is strictly pH-dependent, and that FP-2 preferentially binds methemoglobin over hemoglobin. Because the specificity and proteolytic activity of FP-2 toward its multiple targets appears to be pH-dependent, we suggest that environmental pH may play an important role in orchestrating FP-2 function over the different life stages of the parasite. Moreover, it appears that selectivity of FP-2 for methemoglobin may represent an evolutionary adaptation to oxidative stress conditions within the host cell.
WOS关键词	CYSTEINE PROTEASE FALCIPAIN-2 ; CRYSTAL-STRUCTURE ; CHAGAS-DISEASE ; MOLECULAR REPLACEMENT ; ANTIMALARIAL-DRUGS ; INHIBITORS ; SPECIFICITY ; CRUZAIN ; PEPTIDE ; QUALITY
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000240031300045
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273510]
专题	新药研究国家重点实验室中科院受体结构与功能重点实验室
通讯作者	Hilgenfeld, Rolf
作者单位	1.Med Univ Lubeck, Inst Biochem, Ctr Struct & Cell Biol Med, D-23538 Lubeck, Germany 2.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med,Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Grad Sch, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Hogg, Tanis,Nagarajan, Krishna,Herzberg, Saskia,et al. Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2006,281(35):25425-25437.
APA	Hogg, Tanis.,Nagarajan, Krishna.,Herzberg, Saskia.,Chen, Lili.,Shen, Xu.,...&Schmidt, Christian L..(2006).Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum.JOURNAL OF BIOLOGICAL CHEMISTRY,281(35),25425-25437.
MLA	Hogg, Tanis,et al."Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum".JOURNAL OF BIOLOGICAL CHEMISTRY 281.35(2006):25425-25437.