3ch2

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Crystal Structure Analysis of SERA5E from plasmodium falciparumCrystal Structure Analysis of SERA5E from plasmodium falciparum

Structural highlights

3ch2 is a 1 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 1.8Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SERA5_PLAF7 Plays an essential role during the asexual blood stage development by controlling the kinetics of merozoite egress from host erythrocytes (PubMed:25599609, PubMed:28683142). Specifically, prevents premature rupture of the parasitophorous vacuole and host erythrocyte membranes (PubMed:28683142).[1] [2] May prevent merozoite phagocytosis by host monocytes via interaction with host VTN at the merozoite surface (By similarity). Plays a role in parasite growth (By similarity).[UniProtKB:P69193] Protease activity is controversial (PubMed:25599609). Has been shown in a number of studies to have protease activity towards a synthetic peptide in vitro (PubMed:13679369, PubMed:24769454, PubMed:29716996). Has also been shown to lack protease activity towards a synthetic peptide in vitro (PubMed:25599609).[3] [4] [5] [6]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The sera genes of the malaria-causing parasite Plasmodium encode a family of unique proteins that are maximally expressed at the time of egress of parasites from infected red blood cells. These multi-domain proteins are unique, containing a central papain-like cysteine-protease fragment enclosed between the disulfide-linked N- and C-terminal domains. However, the central fragment of several members of this family, including serine repeat antigen 5 (SERA5), contains a serine (S596) in place of the active-site cysteine. Here we report the crystal structure of the central protease-like domain of Plasmodium falciparum SERA5, revealing a number of anomalies in addition to the putative nucleophilic serine: (1) the structure of the putative active site is not conducive to binding substrate in the canonical cysteine-protease manner; (2) the side chain of D594 restricts access of substrate to the putative active site; and (3) the S(2) specificity pocket is occupied by the side chain of Y735, reducing this site to a small depression on the protein surface. Attempts to determine the structure in complex with known inhibitors were not successful. Thus, despite having revealed its structure, the function of the catalytic domain of SERA5 remains an enigma.

Structural insights into the protease-like antigen Plasmodium falciparum SERA5 and its noncanonical active-site serine.,Hodder AN, Malby RL, Clarke OB, Fairlie WD, Colman PM, Crabb BS, Smith BJ J Mol Biol. 2009 Sep 11;392(1):154-65. Epub 2009 Jul 8. PMID:19591843[7]

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

References

  1. ↑ Stallmach R, Kavishwar M, Withers-Martinez C, Hackett F, Collins CR, Howell SA, Yeoh S, Knuepfer E, Atid AJ, Holder AA, Blackman MJ. Plasmodium falciparum SERA5 plays a non-enzymatic role in the malarial asexual blood-stage lifecycle. Mol Microbiol. 2015 Apr;96(2):368-87. PMID:25599609 doi:10.1111/mmi.12941
  2. ↑ Collins CR, Hackett F, Atid J, Tan MSY, Blackman MJ. The Plasmodium falciparum pseudoprotease SERA5 regulates the kinetics and efficiency of malaria parasite egress from host erythrocytes. PLoS Pathog. 2017 Jul 6;13(7):e1006453. PMID:28683142 doi:10.1371/journal.ppat.1006453
  3. ↑ Hodder AN, Drew DR, Epa VC, Delorenzi M, Bourgon R, Miller SK, Moritz RL, Frecklington DF, Simpson RJ, Speed TP, Pike RN, Crabb BS. Enzymic, phylogenetic, and structural characterization of the unusual papain-like protease domain of Plasmodium falciparum SERA5. J Biol Chem. 2003 Nov 28;278(48):48169-77. PMID:13679369 doi:10.1074/jbc.M306755200
  4. ↑ Kanodia S, Kumar G, Rizzi L, Pedretti A, Hodder AN, Romeo S, Malhotra P. Synthetic peptides derived from the C-terminal 6kDa region of Plasmodium falciparum SERA5 inhibit the enzyme activity and malaria parasite development. Biochim Biophys Acta. 2014 Sep;1840(9):2765-75. PMID:24769454 doi:10.1016/j.bbagen.2014.04.013
  5. ↑ Stallmach R, Kavishwar M, Withers-Martinez C, Hackett F, Collins CR, Howell SA, Yeoh S, Knuepfer E, Atid AJ, Holder AA, Blackman MJ. Plasmodium falciparum SERA5 plays a non-enzymatic role in the malarial asexual blood-stage lifecycle. Mol Microbiol. 2015 Apr;96(2):368-87. PMID:25599609 doi:10.1111/mmi.12941
  6. ↑ Iyer GR, Singh S, Kaur I, Agarwal S, Siddiqui MA, Bansal A, Kumar G, Saini E, Paul G, Mohmmed A, Chitnis CE, Malhotra P. Calcium-dependent phosphorylation of Plasmodium falciparum serine repeat antigen 5 triggers merozoite egress. J Biol Chem. 2018 Jun 22;293(25):9736-9746. PMID:29716996 doi:10.1074/jbc.RA117.001540
  7. ↑ Hodder AN, Malby RL, Clarke OB, Fairlie WD, Colman PM, Crabb BS, Smith BJ. Structural insights into the protease-like antigen Plasmodium falciparum SERA5 and its noncanonical active-site serine. J Mol Biol. 2009 Sep 11;392(1):154-65. Epub 2009 Jul 8. PMID:19591843 doi:10.1016/j.jmb.2009.07.007

3ch2, resolution 1.80Å

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