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Crystal structure of histo‐aspartic protease (HAP) from Plasmodium falciparum
Author(s) -
BHAUMIK PRASENJIT,
Xiao Huogen,
Parr Charity,
Yada Rickey,
Gustchina Alla,
Wlodawer Alexander
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.675.4
Subject(s) - pepstatin , active site , plasmodium falciparum , chemistry , protease , proteases , binding site , serine protease , biochemistry , enzyme , stereochemistry , biology , malaria , immunology
Histo‐aspartic protease (HAP) from Plasmodium falciparum is involved in hemoglobin degradation by the parasite, and thus offers a promising target for antimalarial drug development. The crystal structures of the recombinant HAP, as apoenzyme and complexes with two inhibitors, pepstatin A and KNI‐10006, have been solved at 2.5, 3.3, and 3.0 Åresolution, respectively. In the apoenzyme crystals HAP forms a tight dimer, not seen before in any aspartic proteases, with the flaps that cover the active sites (residues 70‐83) adopting an open conformation. Unexpectedly, the active site of the apoenzyme was found to contain a zinc ion tightly bound to the two active site residues, His32 and Asp215 from one monomer, and to Glu278A from the other monomer, with the coordination resembling its counterparts in metalloproteases. The flap is closed in the structure of pepstatin A complex and Lys76, uniquely present at the tip of the flap in HAP, interacts with the inhibitor. The observed mode of binding of pepstatin A in the HAP active site disproves the previously proposed hypothesis that HAP is a serine protease. The binding mode of KNI‐10006 to HAP is very unusual compared to other members of the KNI series binding to aspartic proteases. The novel features of the active site of HAP should allow designing specific inhibitors that could be developed into antimalarial drugs.