3T8V

A bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases

3T8V の概要

• エントリーDOI: 10.2210/pdb3t8v/pdb
• 関連するPDBエントリー: 3EBG 3T8W
• 分子名称: M1 family aminopeptidase, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: m1 alanyl-aminopeptidase, protease, metallo-aminopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Plasmodium falciparum
• 細胞内の位置: Cytoplasm: O96935
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 105530.94

構造登録者

McGowan, S.,Klemba, M.,Greebaum, D.C. (登録日: 2011-08-01, 公開日: 2011-09-28, 最終更新日: 2024-03-20)

主引用文献

Harbut, M.B.,Velmourougane, G.,Dalal, S.,Reiss, G.,Whisstock, J.C.,Onder, O.,Brisson, D.,McGowan, S.,Klemba, M.,Greenbaum, D.C.
Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases
Proc.Natl.Acad.Sci.USA, 108:E526-E534, 2011

PubMed Abstract: Malaria causes worldwide morbidity and mortality, and while chemotherapy remains an excellent means of malaria control, drug-resistant parasites necessitate the discovery of new antimalarials. Peptidases are a promising class of drug targets and perform several important roles during the Plasmodium falciparum erythrocytic life cycle. Herein, we report a multidisciplinary effort combining activity-based protein profiling, biochemical, and peptidomic approaches to functionally analyze two genetically essential P. falciparum metallo-aminopeptidases (MAPs), PfA-M1 and Pf-LAP. Through the synthesis of a suite of activity-based probes (ABPs) based on the general MAP inhibitor scaffold, bestatin, we generated specific ABPs for these two enzymes. Specific inhibition of PfA-M1 caused swelling of the parasite digestive vacuole and prevented proteolysis of hemoglobin (Hb)-derived oligopeptides, likely starving the parasite resulting in death. In contrast, inhibition of Pf-LAP was lethal to parasites early in the life cycle, prior to the onset of Hb degradation suggesting that Pf-LAP has an essential role outside of Hb digestion.

PubMed: 21844374
DOI: 10.1073/pnas.1105601108

実験手法

X-RAY DIFFRACTION (1.8 Å)