4X2U

X-ray crystal structure of the orally available aminopeptidase inhibitor, Tosedostat, bound to the M1 Alanyl Aminopeptidase from P. falciparum

Summary for 4X2U

• Entry DOI: 10.2210/pdb4x2u/pdb
• Related: 3EBG 3EBH 4X2T
• Descriptor: M1 family aminopeptidase, ZINC ION, (2S)-({(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl}amino)(phenyl)ethanoic acid, ... (6 entities in total)
• Functional Keywords: m1 alanyl-aminopeptidase, protease, inhibitor, antimalarial, plasmodium falciparum, tosedostat, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Plasmodium falciparum FcB1/Columbia
• Total number of polymer chains: 1
• Total formula weight: 104869.35

Authors

Drinkwater, N.,McGowan, S. (deposition date: 2014-11-27, release date: 2015-02-18, Last modification date: 2023-09-27)

Primary citation

Drinkwater, N.,Bamert, R.S.,Sivaraman, K.K.,Paiardini, A.,McGowan, S.
X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17.
Proteins, 83:789-795, 2015

PubMed Abstract: New anti-malarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases, PfA-M1 and PfA-M17, is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here, we describe the crystal structures of PfA-M1 and PfA-M17 bound to chemotherapeutic agent Tosedostat. The inhibitor occupies the enzymes' putative product egress channels in addition to the substrate binding pockets; however, adopts different binding poses when bound to PfA-M1 and PfA-M17. These findings will be valuable for the continued development of selective inhibitors of PfA-M1 and PfA-M17.

PubMed: 25645579
DOI: 10.1002/prot.24771

Experimental method

X-RAY DIFFRACTION (1.5 Å)