3T8W

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

Summary for 3T8W

• Entry DOI: 10.2210/pdb3t8w/pdb
• Related: 3KQX 3T8V
• Descriptor: M17 leucyl aminopeptidase, CARBONATE ION, ZINC ION, ... (8 entities in total)
• Functional Keywords: m17-leucyl aminopeptidase, protease, metallo-aminopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 12
• Total formula weight: 730397.77

Authors

McGowan, S.,Klemba, M.,Greebaum, D.C. (deposition date: 2011-08-01, release date: 2011-09-28, Last modification date: 2024-03-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)