Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum | |
Hogg, Tanis; Nagarajan, Krishna; Herzberg, Saskia; Chen, Lili![]() ![]() ![]() | |
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. |
个性服务 |
查看访问统计 |
相关权益政策 |
暂无数据 |
收藏/分享 |
除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。
修改评论