3T8V
A bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases
Summary for 3T8V
Entry DOI | 10.2210/pdb3t8v/pdb |
Related | 3EBG 3T8W |
Descriptor | M1 family aminopeptidase, ZINC ION, MAGNESIUM ION, ... (5 entities in total) |
Functional Keywords | m1 alanyl-aminopeptidase, protease, metallo-aminopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
Biological source | Plasmodium falciparum |
Cellular location | Cytoplasm: O96935 |
Total number of polymer chains | 1 |
Total formula weight | 105530.94 |
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 Cited by 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: 21844374DOI: 10.1073/pnas.1105601108 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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