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Title: Crystal Structure of the Leishmania Major Phosphodiesterase LmjPDEB1 and Insight into the Design of hte Parasite-Selective Inhibitors

Abstract

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 Angstroms 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.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
960128
Report Number(s):
BNL-83114-2009-JA
TRN: US201016%%1272
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Microbiology; Journal Volume: 66; Journal Issue: 4
Country of Publication:
United States
Language:
English
Subject:
08 HYDROGEN; 36 MATERIALS SCIENCE; APOPTOSIS; CELL PROLIFERATION; CHEMOTHERAPY; CRYSTAL STRUCTURE; DESIGN; GLUTAMINE; HYDROGEN; KINETICS; PHENYLALANINE; PHOSPHODIESTERASES; PUBLIC HEALTH; RESIDUES; RESOLUTION; PARASITES; national synchrotron light source

Citation Formats

Wang,H., Yan, Z., Geng, J., Kunz, S., Seebeck, T., and Ke, H. Crystal Structure of the Leishmania Major Phosphodiesterase LmjPDEB1 and Insight into the Design of hte Parasite-Selective Inhibitors. United States: N. p., 2007. Web. doi:10.1111/j.1365-2958.2007.05976.x.
Wang,H., Yan, Z., Geng, J., Kunz, S., Seebeck, T., & Ke, H. Crystal Structure of the Leishmania Major Phosphodiesterase LmjPDEB1 and Insight into the Design of hte Parasite-Selective Inhibitors. United States. doi:10.1111/j.1365-2958.2007.05976.x.
Wang,H., Yan, Z., Geng, J., Kunz, S., Seebeck, T., and Ke, H. Mon . "Crystal Structure of the Leishmania Major Phosphodiesterase LmjPDEB1 and Insight into the Design of hte Parasite-Selective Inhibitors". United States. doi:10.1111/j.1365-2958.2007.05976.x.
@article{osti_960128,
title = {Crystal Structure of the Leishmania Major Phosphodiesterase LmjPDEB1 and Insight into the Design of hte Parasite-Selective Inhibitors},
author = {Wang,H. and Yan, Z. and Geng, J. and Kunz, S. and Seebeck, T. and Ke, H.},
abstractNote = {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 Angstroms 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.},
doi = {10.1111/j.1365-2958.2007.05976.x},
journal = {Molecular Microbiology},
number = 4,
volume = 66,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}