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Crystal structures of the histo-aspartic protease (HAP) from Plasmodium falciparum.

Bhaumik P, Xiao H, Parr CL, Kiso Y, Gustchina A, Yada RY, Wlodawer A
J Mol Biol 388 520-40 (2009)
Related entries: 3fns, 3fnu

Cited: 28 times
EuropePMC logo PMID: 19285084

Abstract

The structures of recombinant histo-aspartic protease (HAP) from malaria-causing parasite Plasmodium falciparum as apoenzyme and in complex with two inhibitors, pepstatin A and KNI-10006, were solved at 2.5-, 3.3-, and 3.05-A resolutions, respectively. In the apoenzyme crystals, HAP forms a tight dimer not seen previously in any aspartic protease. The interactions between the monomers affect the conformation of two flexible loops, the functionally important "flap" (residues 70-83) and its structural equivalent in the C-terminal domain (residues 238-245), as well as the orientation of helix 225-235. The flap is found in an open conformation in the apoenzyme. Unexpectedly, the active site of the apoenzyme contains a zinc ion tightly bound to His32 and Asp215 from one monomer and to Glu278A from the other monomer, with the coordination of Zn resembling that seen in metalloproteases. The flap is closed in the structure of the pepstatin A complex, whereas it is open in the complex with KNI-10006. Although the binding mode of pepstatin A is significantly different from that in other pepsin-like aspartic proteases, its location in the active site makes unlikely the previously proposed hypothesis that HAP is a serine protease. The binding mode of KNI-10006 is unusual compared with the binding of other inhibitors from the KNI series to aspartic proteases. The novel features of the HAP active site could facilitate design of specific inhibitors used in the development of antimalarial drugs.

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  2. Structural studies of vacuolar plasmepsins. Bhaumik P, Gustchina A, Wlodawer A. Biochim Biophys Acta 1824 207-223 (2012)
  3. 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)

Articles - 3fnt mentioned but not cited (7)

  1. Crystal structures of the histo-aspartic protease (HAP) from Plasmodium falciparum. Bhaumik P, Xiao H, Parr CL, Kiso Y, Gustchina A, Yada RY, Wlodawer A. J Mol Biol 388 520-540 (2009)
  2. Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites. Ponsuwanna P, Kochakarn T, Bunditvorapoom D, Kümpornsin K, Otto TD, Ridenour C, Chotivanich K, Wilairat P, White NJ, Miotto O, Chookajorn T. Malar J 15 51 (2016)
  3. Structural insights into the activation and inhibition of histo-aspartic protease from Plasmodium falciparum. Bhaumik P, Xiao H, Hidaka K, Gustchina A, Kiso Y, Yada RY, Wlodawer A. Biochemistry 50 8862-8879 (2011)
  4. Understanding the structural basis of substrate recognition by Plasmodium falciparum plasmepsin V to aid in the design of potent inhibitors. Bedi RK, Patel C, Mishra V, Xiao H, Yada RY, Bhaumik P. Sci Rep 6 31420 (2016)
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  1. From crystal to compound: structure-based antimalarial drug discovery. Drinkwater N, McGowan S. Biochem J 461 349-369 (2014)
  2. Methods Used to Investigate the Plasmodium falciparum Digestive Vacuole. Edgar RCS, Counihan NA, McGowan S, de Koning-Ward TF. Front Cell Infect Microbiol 11 829823 (2021)

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  1. Overexpression of plasmepsin II and plasmepsin III does not directly cause reduction in Plasmodium falciparum sensitivity to artesunate, chloroquine and piperaquine. Loesbanluechai D, Kotanan N, de Cozar C, Kochakarn T, Ansbro MR, Chotivanich K, White NJ, Wilairat P, Lee MCS, Gamo FJ, Sanz LM, Chookajorn T, Kümpornsin K. Int J Parasitol Drugs Drug Resist 9 16-22 (2019)
  2. Flap dynamics of plasmepsin proteases: insight into proposed parameters and molecular dynamics. Karubiu W, Bhakat S, Bhakat S, McGillewie L, Soliman ME. Mol Biosyst 11 1061-1066 (2015)
  3. Crystal structures of the free and inhibited forms of plasmepsin I (PMI) from Plasmodium falciparum. Bhaumik P, Horimoto Y, Xiao H, Miura T, Hidaka K, Kiso Y, Wlodawer A, Yada RY, Gustchina A. J Struct Biol 175 73-84 (2011)
  4. Functional profiling, identification, and inhibition of plasmepsins in intraerythrocytic malaria parasites. Liu K, Shi H, Xiao H, Chong AG, Bi X, Chang YT, Tan KS, Yada RY, Yao SQ. Angew Chem Int Ed Engl 48 8293-8297 (2009)
  5. Flap flexibility amongst plasmepsins I, II, III, IV, and V: Sequence, structural, and molecular dynamics analyses. McGillewie L, Soliman ME. Proteins 83 1693-1705 (2015)
  6. Insight into selectivity of peptidomimetic inhibitors with modified statine core for plasmepsin II of Plasmodium falciparum over human cathepsin D. Dali B, Keita M, Megnassan E, Frecer V, Miertus S. Chem Biol Drug Des 79 411-430 (2012)
  7. Crystal structure of a putative aspartic proteinase domain of the Mycobacterium tuberculosis cell surface antigen PE_PGRS16. Barathy DV, Suguna K. FEBS Open Bio 3 256-262 (2013)
  8. FAM105A/OTULINL Is a Pseudodeubiquitinase of the OTU-Class that Localizes to the ER Membrane. Ceccarelli DF, Ivantsiv S, Mullin AA, Coyaud E, Manczyk N, Maisonneuve P, Kurinov I, Zhao L, Go C, Gingras AC, Raught B, Cordes S, Sicheri F. Structure 27 1000-1012.e6 (2019)
  9. Discovery of non-peptide inhibitors of Plasmepsin II by structure-based virtual screening. Song Y, Jin H, Liu X, Zhu L, Huang J, Li H. Bioorg Med Chem Lett 23 2078-2082 (2013)
  10. Disulfide linkages in Plasmodium falciparum plasmepsin-i are essential elements for its processing activity and multi-milligram recombinant production yield. Lolupiman S, Siripurkpong P, Yuvaniyama J. PLoS One 9 e89424 (2014)
  11. A Perspective on Thiazolidinone Scaffold Development as a New Therapeutic Strategy for Toxoplasmosis. Rocha-Roa C, Molina D, Cardona N. Front Cell Infect Microbiol 8 360 (2018)
  12. Activation mechanism of plasmepsins, pepsin-like aspartic proteases from Plasmodium, follows a unique trans-activation pathway. Rathore I, Mishra V, Patel C, Xiao H, Gustchina A, Wlodawer A, Yada RY, Bhaumik P. FEBS J 288 678-698 (2021)
  13. Deciphering the mechanism of potent peptidomimetic inhibitors targeting plasmepsins - biochemical and structural insights. Mishra V, Rathore I, Arekar A, Sthanam LK, Xiao H, Kiso Y, Sen S, Patankar S, Gustchina A, Hidaka K, Wlodawer A, Yada RY, Bhaumik P. FEBS J 285 3077-3096 (2018)
  14. Enzymatic Characterization of Recombinant Food Vacuole Plasmepsin 4 from the Rodent Malaria Parasite Plasmodium berghei. Liu P, Robbins AH, Marzahn MR, McClung SH, Yowell CA, Stevens SM, Dame JB, Dunn BM. PLoS One 10 e0141758 (2015)
  15. Optimization of plasmepsin inhibitor by focusing on similar structural feature with chloroquine to avoid drug-resistant mechanism of Plasmodium falciparum. Miura T, Hidaka K, Azai Y, Kashimoto K, Kawasaki Y, Chen SE, de Freitas RF, Freire E, Kiso Y. Bioorg Med Chem Lett 24 1698-1701 (2014)
  16. Evaluation of antiplasmodial activity in silico and in vitro of N-acylhydrazone derivatives. Oliveira FA, Pinto ACS, Duarte CL, Taranto AG, Lorenzato Junior E, Cordeiro CF, Carvalho DT, Varotti FP, Fonseca AL. BMC Chem 16 50 (2022)


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