3FNS

Crystal structure of histo-aspartic protease (HAP) from Plasmodium Falciparum

Summary for 3FNS

• Entry DOI: 10.2210/pdb3fns/pdb
• Related: 3FNT 3FNU
• Descriptor: HAP protein, ZINC ION (3 entities in total)
• Functional Keywords: histo-aspartic protease, hap, plasmepsin, aspartic protease, hormone, hydrolase
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 2
• Total formula weight: 75262.95

Authors

Bhaumik, P.,Gustchina, A.,Wlodawer, A. (deposition date: 2008-12-26, release date: 2009-05-12, Last modification date: 2024-10-09)

Primary citation

Bhaumik, P.,Xiao, H.,Parr, C.L.,Kiso, Y.,Gustchina, A.,Yada, R.Y.,Wlodawer, A.
Crystal structures of the histo-aspartic protease (HAP) from Plasmodium falciparum.
J.Mol.Biol., 388:520-540, 2009

PubMed 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.

PubMed: 19285084
DOI: 10.1016/j.jmb.2009.03.011

Experimental method

X-RAY DIFFRACTION (2.5 Å)