Sökning: onr:"swepub:oai:DiVA.org:liu-128265" > Conformational flex...
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000 | 03654naa a2200337 4500 | |
001 | oai:DiVA.org:liu-128265 | |
003 | SwePub | |
008 | 160524s2013 | |||||||||||000 ||eng| | |
024 | 7 | a https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-1282652 URI |
024 | 7 | a https://doi.org/10.1007/s00894-012-1661-32 DOI |
040 | a (SwePub)liu | |
041 | a engb eng | |
042 | 9 SwePub | |
072 | 7 | a ref2 swepub-contenttype |
072 | 7 | a art2 swepub-publicationtype |
100 | 1 | a Franco-Gonzalez, Juan Felipeu Macromolecular Physics Department, Instituto de Estructura de la Materia, CSIC, Madrid, Spain4 aut |
245 | 1 0 | a Conformational flexibility of the ErbB2 ectodomain and trastuzumab antibody complex as revealed by molecular dynamics and principal component analysis. |
264 | c 2012-11-17 | |
264 | 1 | b Springer Science and Business Media LLC,c 2013 |
338 | a print2 rdacarrier | |
520 | a Human epidermal growth factor receptor 2 (ErbB2) is a transmembrane oncoprotein that is over expressed in breast cancer. A successful therapeutic treatment is a monoclonal antibody called trastuzumab which interacts with the ErbB2 extracellular domain (ErbB2-ECD). A better understanding of the detailed structure of the receptor-antibody interaction is indeed of prime interest for the design of more effective anticancer therapies. In order to discuss the flexibility of the complex ErbB2-ECD/trastuzumab, we present, in this study, a multi-nanosecond molecular dynamics simulation (MD) together with an analysis of fluctuations, through a principal component analysis (PCA) of this system. Previous to this step and in order to validate the simulations, we have performed a detailed analysis of the variable antibody domain interactions with the extracellular domain IV of ErbB2. This structure has been statically elucidated by x-ray studies. Indeed, the simulation results are in excellent agreement with the available experimental information during the full trajectory. The PCA shows eigenvector fluctuations resulting in a hinge motion in which domain II and C(H) domains approach each other. This move is likely stabilized by the formation of H-bonds and salt bridge interactions between residues of the dimerization arm in the domain II and trastuzumab residues located in the C(H) domain. Finally, we discuss the flexibility of the MD/PCA model in relation with the static x-ray structure. A movement of the antibody toward the dimerization domain of the ErbB2 receptor is reported for the first time. This finding could have important consequences on the biological action of the monoclonal antibody. | |
650 | 7 | a NATURVETENSKAPx Biologix Biofysik0 (SwePub)106032 hsv//swe |
650 | 7 | a NATURAL SCIENCESx Biological Sciencesx Biophysics0 (SwePub)106032 hsv//eng |
700 | 1 | a Cruz, Victor Lu Macromolecular Physics Department, Instituto de Estructura de la Materia, CSIC, Madrid, Spain4 aut |
700 | 1 | a Ramos, Javieru Macromolecular Physics Department, Instituto de Estructura de la Materia, CSIC, Madrid, Spain4 aut |
700 | 1 | a Martínez-Salazar, Javieru Macromolecular Physics Department, Instituto de Estructura de la Materia, CSIC, Madrid, Spain4 aut |
710 | 2 | a Macromolecular Physics Department, Instituto de Estructura de la Materia, CSIC, Madrid, Spain4 org |
773 | 0 | t Journal of Molecular Modelingd : Springer Science and Business Media LLCg 19:3, s. 1227-1236q 19:3<1227-1236x 1610-2940x 0948-5023 |
856 | 4 | u https://digital.csic.es/bitstream/10261/72093/1/2013-Franco-JMolModel.pdf |
856 | 4 8 | u https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-128265 |
856 | 4 8 | u https://doi.org/10.1007/s00894-012-1661-3 |
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