caa a22 4500 467938571 CHVBK 20180406153005.0 cr unu---uuuuu 170328e20060801xx s 000 0 eng 10.1007/s10822-006-9061-3 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9061-3 Modeling activated states of GPCRs: the rhodopsin template [Elektronische Daten] [Masha Niv, Lucy Skrabanek, Marta Filizola, Harel Weinstein] Activation of G Protein-Coupled Receptors (GPCRs) is an allosteric mechanism triggered by ligand binding and resulting in conformational changes transduced by the transmembrane domain. Models of the activated forms of GPCRs have become increasingly necessary for the development of a clear understanding of signal propagation into the cell. Experimental evidence points to a multiplicity of conformations related to the activation of the receptor, rendered important physiologically by the suggestion that different conformations may be responsible for coupling to different signaling pathways. In contrast to the inactive state of rhodopsin (RHO) for which several high quality X-ray structures are available, the structure-related information for the active states of rhodopsin and all other GPCRs is indirect. We have collected and stored such information in a repository we maintain for activation-specific structural data available for rhodopsin-like GPCRs, http://www.physiology.med.cornell.edu/GPCRactivation/gpcrindex.html . Using these data as structural constraints, we have applied Simulated Annealing Molecular Dynamics to construct a number of different active state models of RHO starting from the known inactive structure. The common features of the models indicate that TM3 and TM5 play an important role in activation, in addition to the well-established rearrangement of TM6. Some of the structural changes observed in these models occur in regions that were not involved in the constraints, and have not been previously tested experimentally; they emerge as interesting candidates for further experimental exploration of the conformational space of activated GPCRs. We show that none of the normal modes calculated from the inactive structure has a dominant contribution along the path of conformational rearrangement from inactive to the active forms of RHO in the models. This result may differentiate rhodopsin from other GPCRs, and the reasons for this difference are discussed in the context of the structural properties and the physiological function of the protein. Springer Science+Business Media B.V., 2006 Niv Masha Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Ave., 10021, New York, NY, USA aut Skrabanek Lucy Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Ave., 10021, New York, NY, USA aut Filizola Marta Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Ave., 10021, New York, NY, USA aut Weinstein Harel Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Ave., 10021, New York, NY, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 437-448 0920-654X 20:7-8<437 2006 20 10822 https://doi.org/10.1007/s10822-006-9061-3 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9061-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Niv Masha Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Ave., 10021, New York, NY, USA aut NATIONALLICENCE 700 1- Skrabanek Lucy Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Ave., 10021, New York, NY, USA aut NATIONALLICENCE 700 1- Filizola Marta Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Ave., 10021, New York, NY, USA aut NATIONALLICENCE 700 1- Weinstein Harel Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Ave., 10021, New York, NY, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 437-448 0920-654X 20:7-8<437 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence SWISSBIB 462708411 BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer