3pnr

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Structure of PbICP-C in complex with falcipain-2Structure of PbICP-C in complex with falcipain-2

Structural highlights

3pnr is a 2 chain structure with sequence from Plasmodium berghei and Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.6Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FPC2A_PLAF7 Cysteine protease which cleaves native host hemoglobin and globin in the food vacuole during the asexual blood stage (PubMed:10887194, PubMed:15070727, PubMed:15964982, PubMed:16777845, PubMed:19357776, PubMed:25791019). The binding to host hemoglobin is pH-sensitive and only occurs at acidic pH (PubMed:16777845). Cleaves ankyrin and protein 4.1, two components of host erythrocyte membrane cytoskeleton required for the stability of the erythrocyte membrane, and thus may be involved in parasite release (PubMed:11463472). Preferentially cleaves substrates which have an arginine or lysine at the P1 position and a leucine or phenylalanine at the P2 position (PubMed:10887194, PubMed:19357776).[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

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 A 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.

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. 2011 Jul 13;19(7):919-29. PMID:21742259[8]

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

References

  1. ↑ Shenai BR, Sijwali PS, Singh A, Rosenthal PJ. Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum. J Biol Chem. 2000 Sep 15;275(37):29000-10. PMID:10887194 doi:10.1074/jbc.M004459200
  2. ↑ Dua M, Raphael P, Sijwali PS, Rosenthal PJ, Hanspal M. Recombinant falcipain-2 cleaves erythrocyte membrane ankyrin and protein 4.1. Mol Biochem Parasitol. 2001 Aug;116(1):95-9. PMID:11463472 doi:10.1016/s0166-6851(01)00306-1
  3. ↑ Sijwali PS, Rosenthal PJ. Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4384-9. PMID:15070727 doi:10.1073/pnas.0307720101
  4. ↑ Pandey KC, Wang SX, Sijwali PS, Lau AL, McKerrow JH, Rosenthal PJ. The Plasmodium falciparum cysteine protease falcipain-2 captures its substrate, hemoglobin, via a unique motif. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9138-43. PMID:15964982 doi:10.1073/pnas.0502368102
  5. ↑ Hogg T, Nagarajan K, Herzberg S, Chen L, Shen X, Jiang H, Wecke M, Blohmke C, Hilgenfeld R, Schmidt CL. Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum. J Biol Chem. 2006 Sep 1;281(35):25425-37. Epub 2006 Jun 15. PMID:16777845 doi:10.1074/jbc.M603776200
  6. ↑ Subramanian S, Hardt M, Choe Y, Niles RK, Johansen EB, Legac J, Gut J, Kerr ID, Craik CS, Rosenthal PJ. Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3. PLoS One. 2009;4(4):e5156. PMID:19357776 doi:10.1371/journal.pone.0005156
  7. ↑ Marques AF, Gomes PS, Oliveira PL, Rosenthal PJ, Pascutti PG, Lima LM. Allosteric regulation of the Plasmodium falciparum cysteine protease falcipain-2 by heme. Arch Biochem Biophys. 2015 May 1;573:92-9. PMID:25791019 doi:10.1016/j.abb.2015.03.007
  8. ↑ Hansen G, Heitmann A, Witt T, Li H, Jiang H, Shen X, Heussler VT, Rennenberg A, Hilgenfeld R. Structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in Plasmodium. Structure. 2011 Jul 13;19(7):919-29. PMID:21742259 doi:10.1016/j.str.2011.03.025

3pnr, resolution 2.60Å

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