Crystal structure of the Leishmania major phosphodiesterase LmjPDEB1 and insight into the design of the parasite-selective inhibitors

• Published in: Molecular microbiology Vol. 66; no. 4; pp. 1029 - 1038
• Main Authors: Wang, Huanchen, Yan, Zier, Geng, Jie, Kunz, Stefan, Seebeck, Thomas, Ke, Hengming
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.11.2007; Blackwell Publishing Ltd; Blackwell Science
• Subjects: 1-Methyl-3-isobutylxanthine - metabolism; Amino Acid Sequence; Animals; Apoptosis; Binding Sites; Biological and medical sciences; Catalysts; Catalytic Domain; Cells; Comparative analysis; Crystal structure; Crystallization; Crystallography, X-Ray; Drug Design; Fundamental and applied biological sciences. Psychology; Humans; Leishmania major; Leishmania major - drug effects; Leishmania major - enzymology; Life cycle. Host-agent relationship. Pathogenesis; Models, Molecular; Molecular Sequence Data; Parasites; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - drug effects; Phosphoric Diester Hydrolases - metabolism; Protein Folding; Protozoa; Public health; Infection; Kinetoplastida; Protozoa; Parasitosis; Leishmania major; Crystalline structure
• DOI: 10.1111/j.1365-2958.2007.05976.x
• ISSN: 0950-382X

Human leishmaniasis is a major public health problem in many countries, but chemotherapy is in an unsatisfactory state. Leishmania major phosphodiesterases (LmjPDEs) have been shown to play important roles in cell proliferation and apoptosis of the parasite. Thus LmjPDE inhibitors may potentially represent a novel class of drugs for the treatment of leishmaniasis. Reported here are the kinetic characterization of the LmjPDEB1 catalytic domain and its crystal structure as a complex with 3-isobutyl-1-methylxanthine (IBMX) at 1.55 Å resolution. The structure of LmjPDEB1 is similar to that of human PDEs. IBMX stacks against the conserved phenylalanine and forms a hydrogen bond with the invariant glutamine, in a pattern common to most inhibitors bound to human PDEs. However, an extensive structural comparison reveals subtle, but significant differences between the active sites of LmjPDEB1 and human PDEs. In addition, a pocket next to the inhibitor binding site is found to be unique to LmjPDEB1. This pocket is isolated by two gating residues in human PDE families, but constitutes a natural expansion of the inhibitor binding pocket in LmjPDEB1. The structure particularity might be useful for the development of parasite-selective inhibitors for the treatment of leishmaniasis.