4R6T: Structure Of The M17 Leucyl Aminopeptidase From Malaria Complexed With A Hydroxamic Acid-based Inhibitor

Citation:
Abstract
Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.
PDB ID: 4R6TDownload
MMDB ID: 124369
PDB Deposition Date: 2014/8/26
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
Similar Structures:
Biological Unit for 4R6T: hexameric; determined by author and by software (PISA)
Molecular Components in 4R6T
Label Count Molecule
Proteins (6 molecules)
6
M17 Leucyl Aminopeptidase
Molecule annotation
Chemicals (48 molecules)
1
12
2
6
3
12
4
6
5
12
* Click molecule labels to explore molecular sequence information.

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