Structural basis of p21H-ras molecular switch inhibition by a neutralizing antibody |
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| Institution: | 1. Dipartimento di Matematica e Fisica and Interdisciplinary Laboratories for Advanced Materials Physics, Universitá Cattolica, via Musei 41, 25121 Brescia, and INFN, Sezione di Pavia, Italy;2. Instituto de Física, Universidad Autónoma de Puebla, Apt. Postal J-48, Puebla, Pue., 72570, Mexico;3. Department of Physics, Yeshiva University, 245 Lexington Ave, New York, NY 10016, USA;4. NSCL and Department of Physics and Astronomy, Michigan State University, East Lansing, MI 48824-1321, USA;1. Department of Chemical Engineering, University of the Basque Country UPV/EHU, P.O. Box 644 E48080 Bilbao, Spain;2. Institute of Combustion and Power Plant Technology, University of Stuttgart, Pfaffenwaldring 23, D-70569 Stuttgart, Germany;3. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain;4. Department of Energy and Power Engineering, Tsinghua University, Beijing, China;1. Key Laboratory of Inorganic Functional Materials and Devices, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai, 200050, People’s Republic of China;2. State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai, 200050, People’s Republic of China;3. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China;4. Fujian Key Laboratory of Highly-reliable Capacitors and Ceramic Materials, Quanzhou, 362000 Fujian, People’s Republic of China |
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| Abstract: | The ras oncogene product p21 functions as a molecular switch in the early section of the signal transduction pathway that is involved in cell growth and differentiation. When the protein is in its GTP-complexed form it is active in signal transduction, whereas it is inactive in its GDP-complexed form. The transforming activity of p21ras is neutralized by the mouse monoclonal antibody Y13-259, possibly by preventing GDP-GTP exchange. A molecular model of the variable fragment of Y13-259 has been derived using a knowledge-based prediction approach and computer-assisted modeling techniques. An analysis of this model while complexed with p21ras/(GDP) indicated that the two molecular switch regions are constrained by complex formation. Antibody binding inhibits GDP-GTP exchange through a mechanism of steric hindrance. Having identified necessary bound sites for inhibition, and explored their electrostatic properties, it should be possible to proceed with the design of antibody mimics as therapeutic agents in cancer control. |
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