4x2t

X-ray crystal structure of the orally available aminopeptidase inhibitor, Tosedostat, bound to the M17 Leucyl Aminopeptidase from P. falciparumX-ray crystal structure of the orally available aminopeptidase inhibitor, Tosedostat, bound to the M17 Leucyl Aminopeptidase from P. falciparum

Structural highlights

4x2t is a 12 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.729Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

AMPL_PLAF7 Aminopeptidase which preferentially cleaves leucine residues from the N-terminus of peptides (PubMed:17107951, PubMed:21844374, PubMed:22359643, PubMed:33536500, PubMed:34133730). Also, has some activity towards tryptophan and methionine and to a lesser extent towards phenylalanine (PubMed:17107951, PubMed:22359643, PubMed:34133730). Has very low activity or no activity towards the other amino acids (PubMed:17107951, PubMed:22359643, PubMed:34133730). In addition, cleaves the Cys-Gly dipeptide, probably as part of the glutathione regulation pathway; cleavage only occurs in the presence of Mn(2+) (PubMed:33303633). During the asexual blood stage, plays a role in the final step of host hemoglobin catabolism, by cleaving hemoglobin-derived oligopeptides providing a source of amino acids for the parasite protein synthesis and for the maintenance of osmotic homeostasis (PubMed:34133730). During the asexual blood stage, may also play a role during the ring-trophozoite transition (PubMed:21844374).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

New antimalarial 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. This article is protected by copyright. All rights reserved.

X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17.,Drinkwater N, Bamert RS, Kannan Sivaraman K, Paiardini A, McGowan S Proteins. 2015 Feb 2. doi: 10.1002/prot.24771. PMID:25645579^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stack CM, Lowther J, Cunningham E, Donnelly S, Gardiner DL, Trenholme KR, Skinner-Adams TS, Teuscher F, Grembecka J, Mucha A, Kafarski P, Lua L, Bell A, Dalton JP. Characterization of the Plasmodium falciparum M17 leucyl aminopeptidase. A protease involved in amino acid regulation with potential for antimalarial drug development. J Biol Chem. 2007 Jan 19;282(3):2069-80. PMID:17107951 doi:10.1074/jbc.M609251200
↑ Harbut MB, Velmourougane G, Dalal S, Reiss G, Whisstock JC, Onder O, Brisson D, McGowan S, Klemba M, Greenbaum DC. Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases. Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E526-34. Epub 2011 Aug 15. PMID:21844374 doi:10.1073/pnas.1105601108
↑ Poreba M, McGowan S, Skinner-Adams TS, Trenholme KR, Gardiner DL, Whisstock JC, To J, Salvesen GS, Dalton JP, Drag M. Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum. PLoS One. 2012;7(2):e31938. PMID:22359643 doi:10.1371/journal.pone.0031938
↑ Malcolm TR, Belousoff MJ, Venugopal H, Borg NA, Drinkwater N, Atkinson SC, McGowan S. Active site metals mediate an oligomeric equilibrium in Plasmodium M17 aminopeptidases. J Biol Chem. 2020 Dec 10. pii: RA120.016313. doi: 10.1074/jbc.RA120.016313. PMID:33303633 doi:http://dx.doi.org/10.1074/jbc.RA120.016313
↑ Mathew R, Wunderlich J, Thivierge K, Cwiklinski K, Dumont C, Tilley L, Rohrbach P, Dalton JP. Biochemical and cellular characterisation of the Plasmodium falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP). Sci Rep. 2021 Feb 3;11(1):2854. PMID:33536500 doi:10.1038/s41598-021-82499-4
↑ Malcolm TR, Swiderska KW, Hayes BK, Webb CT, Drag M, Drinkwater N, McGowan S. Mapping the substrate specificity of the Plasmodium M1 and M17 aminopeptidases. Biochem J. 2021 Jul 16;478(13):2697-2713. PMID:34133730 doi:10.1042/BCJ20210172
↑ Drinkwater N, Bamert RS, Kannan Sivaraman 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. 2015 Feb 2. doi: 10.1002/prot.24771. PMID:25645579 doi:http://dx.doi.org/10.1002/prot.24771

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OCA

[1] Stack CM, Lowther J, Cunningham E, Donnelly S, Gardiner DL, Trenholme KR, Skinner-Adams TS, Teuscher F, Grembecka J, Mucha A, Kafarski P, Lua L, Bell A, Dalton JP. Characterization of the Plasmodium falciparum M17 leucyl aminopeptidase. A protease involved in amino acid regulation with potential for antimalarial drug development. J Biol Chem. 2007 Jan 19;282(3):2069-80. PMID:17107951 doi:10.1074/jbc.M609251200

[2] Harbut MB, Velmourougane G, Dalal S, Reiss G, Whisstock JC, Onder O, Brisson D, McGowan S, Klemba M, Greenbaum DC. Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases. Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E526-34. Epub 2011 Aug 15. PMID:21844374 doi:10.1073/pnas.1105601108

[3] Poreba M, McGowan S, Skinner-Adams TS, Trenholme KR, Gardiner DL, Whisstock JC, To J, Salvesen GS, Dalton JP, Drag M. Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum. PLoS One. 2012;7(2):e31938. PMID:22359643 doi:10.1371/journal.pone.0031938

[4] Malcolm TR, Belousoff MJ, Venugopal H, Borg NA, Drinkwater N, Atkinson SC, McGowan S. Active site metals mediate an oligomeric equilibrium in Plasmodium M17 aminopeptidases. J Biol Chem. 2020 Dec 10. pii: RA120.016313. doi: 10.1074/jbc.RA120.016313. PMID:33303633 doi:http://dx.doi.org/10.1074/jbc.RA120.016313

[5] Mathew R, Wunderlich J, Thivierge K, Cwiklinski K, Dumont C, Tilley L, Rohrbach P, Dalton JP. Biochemical and cellular characterisation of the Plasmodium falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP). Sci Rep. 2021 Feb 3;11(1):2854. PMID:33536500 doi:10.1038/s41598-021-82499-4

[6] Malcolm TR, Swiderska KW, Hayes BK, Webb CT, Drag M, Drinkwater N, McGowan S. Mapping the substrate specificity of the Plasmodium M1 and M17 aminopeptidases. Biochem J. 2021 Jul 16;478(13):2697-2713. PMID:34133730 doi:10.1042/BCJ20210172

[7] Drinkwater N, Bamert RS, Kannan Sivaraman 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. 2015 Feb 2. doi: 10.1002/prot.24771. PMID:25645579 doi:http://dx.doi.org/10.1002/prot.24771

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