Membrane proteins play an essential role in controlling the movement of material and information in and out of the cell, in determining the flow and use of energy, as well as in triggering the initiation of numerous signaling pathways. To fulfill these roles, conformational and interaction dynamics exert a dominant influence on their functional behavior, for it is the interplay between structure and dynamics what ultimately defines their function. The Membrane Protein Structural Dynamics Consortium (MPSDC) is proposed as a highly interactive, tightly integrated and multidisciplinary effort focused on elucidating the relationship between structure, dynamics and function in a variety of membrane proteins. The MMPSD will be organized around multidisciplinary project teams formed by investigators from 14 institutions in five different countries. These teams will study major mechanistic questions associated with membrane protein function as it relates to two major areas: energy transduction in signaling (ion channels and receptors) and energy inter-conversion (transporters and pumps). Ultimately, our goal is to decode the general mechanistic principles that govern protein movement and its associated fluctuation dynamics by dissecting and analyzing the molecular and dynamical bases of these functions at an unprecedented and quantitative level, as well as exploiting this information to engineer altered and novel activities into membrane protein frameworks to rationally evolve new functions. To accomplish its goals, the MPSDC will develop in parallel a set of tools, concepts and reagents to: 1) Apply state of the art spectroscopic methods (Magnetic Resonance, Fluorescence, 2D-IR) to follow conformational changes and dynamics of the determined structures;2) Correlate dynamic measurements with high-resolution ensemble and single molecule functional measurements;and 3) Design and implement novel computational approaches to link static and dynamic data with function. Six core facilities will feed and interconnect with the individual projects in a highly interactive way. The cores will act as both, """"""""innovation incubators"""""""" and research support centers by providing service and expertise In these critical areas: Membrane protein expression, the establishment of chemical synthesis capabilities for probes and detergents, the generation of a variety of binders and other crystallization chaperones and other target binders, the development of common computational tools to interpret and integrate the wealth of experimental data, the generation of novel, highly specific synthetic toxins and the continuous discovery of novel targets through the use of metagenomics tools.
The interplay between structure and dynamics what ultimately defines a biological system's functional mechanism. Knowledge of how these fundamental phenomena influence the way membrane proteins function will be required to understand both the complex web of signaling and energy transduction mechanisms required for normal cellular function and their pathologies.
| Boulanger, Eliot; Huang, Lei; Rupakheti, Chetan et al. (2018) Optimized Lennard-Jones Parameters for Druglike Small Molecules. J Chem Theory Comput 14:3121-3131 |
| LeVine, Michael V; Cuendet, Michel A; Razavi, Asghar M et al. (2018) Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter. Biophys J 114:10-14 |
| Diver, Melinda M; Pedi, Leanne; Koide, Akiko et al. (2018) Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT. Nature 553:526-529 |
| Carnevale, Lauren N; Arango, Andres S; Arnold, William R et al. (2018) Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase. Biochemistry 57:6489-6499 |
| Molinarolo, Steven; Lee, Sora; Leisle, Lilia et al. (2018) Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel. J Biol Chem 293:4981-4992 |
| Paz, Aviv; Claxton, Derek P; Kumar, Jay Prakash et al. (2018) Conformational transitions of the sodium-dependent sugar transporter, vSGLT. Proc Natl Acad Sci U S A 115:E2742-E2751 |
| Brugarolas, Pedro; Sánchez-RodrÃguez, Jorge E; Tsai, Hsiu-Ming et al. (2018) Development of a PET radioligand for potassium channels to image CNS demyelination. Sci Rep 8:607 |
| Mahinthichaichan, Paween; Morris, Dylan M; Wang, Yi et al. (2018) Selective Permeability of Carboxysome Shell Pores to Anionic Molecules. J Phys Chem B 122:9110-9118 |
| Li, Jing; Ostmeyer, Jared; Cuello, Luis G et al. (2018) Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel. J Gen Physiol 150:1408-1420 |
| Kerr, Daniel; Tietjen, Gregory T; Gong, Zhiliang et al. (2018) Sensitivity of peripheral membrane proteins to the membrane context: A case study of phosphatidylserine and the TIM proteins. Biochim Biophys Acta Biomembr 1860:2126-2133 |
Showing the most recent 10 out of 282 publications
