Download MendeleyRecombinant plasmepsin 1 from the human malaria parasite plasmodium falciparum: enzymatic characterization, active site inhibitor design, and structural analysis.
Liu, P., Marzahn, M.R., Robbins, A.H., Gutierrez-de-Teran, H., Rodriguez, D., McClung, S.H., Stevens, S.M., Yowell, C.A., Dame, J.B., McKenna, R., Dunn, B.M.(2009) Biochemistry 48: 4086-4099
- PubMed: 19271776
- DOI: https://doi.org/10.1021/bi802059r
- Primary Citation of Related Structures:
2R9B - PubMed Abstract:
A mutated form of truncated proplasmepsin 1 (proPfPM1) from the human malaria parasite Plasmodium falciparum, proPfPM1 K110pN, was generated and overexpressed in Escherichia coli. The automaturation process was carried out at pH 4.0 and 4.5, and the optimal catalytic pH of the resulting mature PfPM1 was determined to be pH 5.5. This mature PfPM1 showed comparable binding affinity to peptide substrates and inhibitors with the naturally occurring form isolated from parasites. The S3-S3' subsite preferences of the recombinant mature PfPM1 were explored using combinatorial chemistry based peptide libraries. On the basis of the results, a peptidomimetic inhibitor (compound 1) was designed and yielded 5-fold selectivity for binding to PfPM1 versus the homologous human cathepsin D (hcatD). The 2.8 A structure of the PfPM2-compound 1 complex is reported. Modeling studies were conducted using a series of peptidomimetic inhibitors (compounds 1-6, Table 3) and three plasmepsins: the crystal structure of PfPM2, and homology derived models of PfPM1 and PfPM4.
Organizational Affiliation:
Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, Florida 32610-0245, USA.
