Human thrombospondin’s (TSP-1) C-terminal domain opens to interact with the CD-47 receptor: A molecular modeling study
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- 作者：Nicolas Floquet ; Sté ; phane Dedieu ; Laurent Martiny ; Manuel Dauchez ; David Perahia
- 关键词：Thrombospondin ; TSP-1 ; CD-47 ; Normal modes ; Hydrophobic cleft ; Opening motion ; Protein– ; protein interactions ; Docking
- 刊名：Archives of Biochemistry and Biophysics
- 出版年：2008
- 出版时间：1 October 2008
- 年：2008
- 卷：478
- 期：1
- 页码：103-109
- 全文大小：1634 K
文摘
Thrombospondin-1 (TSP-1) interaction with the membranous receptor CD-47 involves the peptide RFYVVMWK (4N-1) located in its C-terminal domain. However, the available X-ray structure of TSP-1 describes this peptide as completely buried into a hydrophobic pocket, preventing any interaction. Where classical standard methods failed, an appropriate approach combining normal mode analysis and an adapted protocol of energy minimization identified the large amplitude motions responsible of the partial solvent exposure of 4N-1. In agreement, the obtained model of the open TSP-1 was further used for protein–protein docking experiments against a homology model generated for CD-47. Considering the multiple applications of the CD-47 receptor as a target, our results open new pharmacological perspectives for the design of TSP-1:CD-47 inhibitors and CD-47 antagonists. We also suggest a common opening mechanism for proteins sharing the same fold as TSP-1. This work also suggests the usefulness of our approach in other topics in which predictions of protein–protein interactions are of importance.