3KR4

Structure of a protease 3

Summary for 3KR4

• Entry DOI: 10.2210/pdb3kr4/pdb
• Related: 3KQX 3KQZ 3KR5
• Descriptor: M17 leucyl aminopeptidase, CARBONATE ION, ZINC ION, ... (8 entities in total)
• Functional Keywords: protease, aminopeptidase, hydrolase
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 12
• Total formula weight: 720166.00

Authors

McGowan, S.,Whisstock, J.C. (deposition date: 2009-11-17, release date: 2010-02-02, Last modification date: 2023-11-01)

Primary citation

McGowan, S.,Oellig, C.A.,Birru, W.A.,Caradoc-Davies, T.T.,Stack, C.M.,Lowther, J.,Skinner-Adams, T.,Mucha, A.,Kafarski, P.,Grembecka, J.,Trenholme, K.R.,Buckle, A.M.,Gardiner, D.L.,Dalton, J.P.,Whisstock, J.C.
Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases
Proc.Natl.Acad.Sci.USA, 107:2449-2454, 2010

PubMed Abstract: Current therapeutics and prophylactics for malaria are under severe challenge as a result of the rapid emergence of drug-resistant parasites. The human malaria parasite Plasmodium falciparum expresses two neutral aminopeptidases, PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. We previously reported the X-ray crystal structure of the monomeric PfA-M1 and proposed a mechanism for substrate entry and free amino acid release from the active site. Here, we present the X-ray crystal structure of the hexameric leucine aminopeptidase, PfA-M17, alone and in complex with two inhibitors with antimalarial activity. The six active sites of the PfA-M17 hexamer are arranged in a disc-like fashion so that they are orientated inwards to form a central catalytic cavity; flexible loops that sit at each of the six entrances to the catalytic cavern function to regulate substrate access. In stark contrast to PfA-M1, PfA-M17 has a narrow and hydrophobic primary specificity pocket which accounts for its highly restricted substrate specificity. We also explicate the essential roles for the metal-binding centers in these enzymes (two in PfA-M17 and one in PfA-M1) in both substrate and drug binding. Our detailed understanding of the PfA-M1 and PfA-M17 active sites now permits a rational approach in the development of a unique class of two-target and/or combination antimalarial therapy.

PubMed: 20133789
DOI: 10.1073/pnas.0911813107

Experimental method

X-RAY DIFFRACTION (2 Å)