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Structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in Plasmodium.

Hansen G, Heitmann A, Witt T, Li H, Jiang H, Shen X, Heussler VT, Rennenberg A, Hilgenfeld R
Structure 19 919-29 (2011)
Cited: 18 times
EuropePMC logo PMID: 21742259

Abstract

Plasmodium cysteine proteases are essential for host-cell invasion and egress, hemoglobin degradation, and intracellular development of the parasite. The temporal, site-specific regulation of cysteine-protease activity is a prerequisite for survival and propagation of Plasmodium. Recently, a new family of inhibitors of cysteine proteases (ICPs) with homologs in at least eight Plasmodium species has been identified. Here, we report the 2.6 Å X-ray crystal structure of the C-terminal, inhibitory domain of ICP from P. berghei (PbICP-C) in a 1:1 complex with falcipain-2, an important hemoglobinase of Plasmodium. The structure establishes Plasmodium ICP as a member of the I42 class of chagasin-like protease inhibitors but with large insertions and differences in the binding mode relative to other family members. Furthermore, the PbICP-C structure explains why host-cell cathepsin B-like proteases and, most likely, also the protease-like domain of Plasmodium SERA5 (serine-repeat antigen 5) are no targets for ICP.

Reviews - 3pnr mentioned but not cited (3)

  1. Cysteine Proteases: Modes of Activation and Future Prospects as Pharmacological Targets. Verma S, Dixit R, Pandey KC. Front Pharmacol 7 107 (2016)
  2. The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. Ogungbe IV, Setzer WN. Molecules 21 E1389 (2016)
  3. Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases. Tušar L, Usenik A, Turk B, Turk D. Int J Mol Sci 22 997 (2021)

Articles - 3pnr mentioned but not cited (4)

  1. Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and Their Association With Artemisinin Resistance. Siddiqui FA, Cabrera M, Wang M, Brashear A, Kemirembe K, Wang Z, Miao J, Chookajorn T, Yang Z, Cao Y, Dong G, Rosenthal PJ, Cui L. J Infect Dis 218 434-442 (2018)
  2. The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site. Machin JM, Kantsadi AL, Vakonakis I. Malar J 18 388 (2019)
  3. Cross-talk between malarial cysteine proteases and falstatin: the BC loop as a hot-spot target. Sundararaj S, Saxena AK, Sharma R, Vashisht K, Sharma S, Anvikar A, Dixit R, Rosenthal PJ, Pandey KC. PLoS One 9 e93008 (2014)
  4. The macromolecular complex of ICP and falcipain-2 from Plasmodium: preparation, crystallization and preliminary X-ray diffraction analysis. Hansen G, Schwarzloh B, Rennenberg A, Heussler VT, Hilgenfeld R. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 1406-1410 (2011)


Reviews citing this publication (1)

  1. Molecular recognition in chemical and biological systems. Persch E, Dumele O, Diederich F. Angew Chem Int Ed Engl 54 3290-3327 (2015)

Articles citing this publication (10)

  1. Synthetic microbial consortia enable rapid assembly of pure translation machinery. Villarreal F, Contreras-Llano LE, Chavez M, Ding Y, Fan J, Pan T, Tan C. Nat Chem Biol 14 29-35 (2018)
  2. Assembly of the eukaryotic PLP-synthase complex from Plasmodium and activation of the Pdx1 enzyme. Guédez G, Hipp K, Windeisen V, Derrer B, Gengenbacher M, Böttcher B, Sinning I, Kappes B, Tews I. Structure 20 172-184 (2012)
  3. Plasmodium yoelii inhibitor of cysteine proteases is exported to exomembrane structures and interacts with yoelipain-2 during asexual blood-stage development. Pei Y, Miller JL, Lindner SE, Vaughan AM, Torii M, Kappe SHI. Cell Microbiol 15 1508-1526 (2013)
  4. Methyl-methoxylpyrrolinone and flavinium nucleus binding signatures on falcipain-2 active site. Omotuyi OI. J Mol Model 20 2386 (2014)
  5. A cysteine protease inhibitor of plasmodium berghei is essential for exo-erythrocytic development. Lehmann C, Heitmann A, Mishra S, Burda PC, Singer M, Prado M, Niklaus L, Lacroix C, Ménard R, Frischknecht F, Stanway R, Sinnis P, Heussler V. PLoS Pathog 10 e1004336 (2014)
  6. Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents. Chakka SK, Kalamuddin M, Sundararaman S, Wei L, Mundra S, Mahesh R, Malhotra P, Mohmmed A, Kotra LP. Bioorg Med Chem 23 2221-2240 (2015)
  7. Structural basis for the immunomodulatory function of cysteine protease inhibitor from human roundworm Ascaris lumbricoides. Mei G, Dong J, Li Z, Liu S, Liu Y, Sun M, Liu G, Su Z, Liu J. PLoS One 9 e96069 (2014)
  8. Dynamical footprint of falcipain-2 catalytic triad in hemoglobin-β-bound state. Omotuyi IO, Hamada T. J Biomol Struct Dyn 33 1027-1036 (2015)
  9. A new piece in the 3D Jigsaw of malaria parasite. Jaskolski M. Structure 19 901-902 (2011)
  10. Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite. Lê HG, Kang JM, Võ TC, Nguyễn TD, Jung M, Shin MK, Yoo WG, Na BK. Pathogens 11 605 (2022)


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