Rational proteomics of PKD1. I. Modeling the three dimensional structure and ligand specificity of the C_lectin binding domain of Polycystin-1. |
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Authors: | Vladimir Pletnev Robert Huether Lukas Habegger Wayne Schultz William Duax |
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Institution: | (1) Institute of Bioorganic Chemistry RAS, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia;(2) Department of Structural Biology, Hauptman-Woodward Medical Research Institute & SUNY at Buffalo, 700 Ellicott St., Buffalo, NY 14203, USA |
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Abstract: | Polycystin-1 (Pc-1) is the 4303 amino acid multi-domain glycoprotein product of the polycystic kidney disease-1 (PKD1) gene.
Mutations in this gene are implicated in 85% of cases of human autosomal dominant polycystic disease. Although the biochemistry
of Pc-1 has been extensively studied its three dimensional structure has yet to be determined. We are combining bioinformatics,
computational and biochemical data to model the 3D structure and function of individual domains of Pc-1. A three dimensional
model of the C-type lectin domain (CLD) of Pc-1 (sequence region 405–534) complexed with galactose (Gal) and a calcium ion
(Ca+2) has been developed (the coordinates are available on request, e-mail: pletnev@hwi.buffalo.edu). The model has α/β structural
organization. It is composed of eight β strands and three α helices, and includes three disulfide bridges. It is consistent
with the observed Ca+2 dependence of sugar binding to CLD and identifies the amino acid side chains (E499, H501, E506, N518, T519 and D520) that
are likely to bind the ligand. The model provides a reliable basis upon which to map functionally important residues using
mutagenic experiments and to refine our knowledge about a preferred sugar ligand and the functional role of the CLD in polycystin-1.
Figure Carbohydrate binding site with bound galactose and calcium ion inC-lectin binding domain of polycystin-1 |
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Keywords: | PKD1 disease Polycystin 1 C_lectin binding domain 3D modeling Bioinformatics |
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