کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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443576 | 692737 | 2010 | 13 صفحه PDF | دانلود رایگان |
Noggin is a major natural extracellular antagonist to bone morphogenetic proteins (BMPs) which binds to BMPs and blocks binding of them to BMP-specific receptors and thus negatively regulates BMP-induced osteoblastic differentiation. Bone morphogenetic proteins (BMPs) signal through heteromeric protein complexes composed of type I and type II serine/threonine kinase receptors. Preventing the BMP-2/noggin interaction will preserve free BMP-2 and enhance the efficacy of BMP-2 to induce bone formation. This work is an attempt to use the current understanding of BMP-2, and its interaction with its receptors and antagonist to design an inhibitor of BMP-2/noggin interaction with the goal of lowering the dose of BMP-2 required in clinical applications. The crystal structure of the BMP-7/noggin complex, the BMP-2/BMP receptor IA ectodomain complex and the extracellular domain of BMP receptor II monomer are known. We modeled the BMP-2 based on the structure of its homologue BMP-7 and its binding complex with noggin. We also modeled a complex of BMP-2/BMPRIA/BMPRII by modeling BMPRII and replacing ActRIIB in the BMP-2/BMPRIA/ActRIIB complex. We then identified the binding region of noggin with BMP-2 and the receptors with BMP-2. From the analysis of structures of these complexes and modeling we identified the key amino acids present in the entire interacting surfaces among these proteins that play important physiological role in the regulation of cell differentiation and bone metabolism. By in silico screening we selected and ranked several compounds that have high theoretical scores to bind to noggin to block BMP–noggin interaction.
Journal: Journal of Molecular Graphics and Modelling - Volume 28, Issue 7, April 2010, Pages 670–682