To understand membrane proteins, one must ultimately be able to visualize how these complex nanoscale molecular machines move and change their shape atom-by-atom as a function of time while they perform their function. Grounded on the understanding that membrane proteins are dynamic entities that evolved to execute complex sets of movements to perform their functions, what is critically needed is a conceptual movie that captures the essential structural rearrangements underlying function. In spite of recent progress, any particular approach, albeit experimental or computational, is too limited to provide complete information about the transient features associated with such conformational transitions. To make a significant leap forward, the quantitative study of membrane protein dynamics requires a synergistic and multi-disciplinary effort. The main task of this 10-year Consortium is to quantitatively address these issues and provide a basic set of mechanistic principles that relate membrane protein structural dynamics to their function based on a set of membrane protein archetypes. In this proposal, we highlight our recent advances in membrane protein crystallization, spectroscopic, biophysical and modeling techniques. Through highly collaborative partnerships that balance technology incubators (the scientific Cores) with specific projects (Bridging and Pilot projects) we have reached a level of applicability to complex systems unimaginable just a decade ago. However, dynamic information must be quantitatively determined to understand function and this requires the application of both known strategies and methods development. Our proposition remains that a tight integration between structural methods, spectroscopic techniques, functional analyses and computational approaches, is required to provide a deep understanding of these nano-machines and their biological roles. In its Phase II, we find ourselves in an excellent position to expand the number of systems under study, their overall complexity and incorporate new experimental and computational techniques. Accordingly, the MPSDC will continue to be organized around multidisciplinary project teams studying major mechanistic questions associated with membrane protein function in nine archetype systems, spanning a multiplicity of energy transduction mechanisms. Furthermore, the research infrastructure in place for phase II will extend the capacity of the Consortium to make further transforming contributions that should define the fundamental principles governing membrane protein function into the next decade

Public Health Relevance

The interplay between structure and molecular dynamics is what ultimately defines a biological system's function. This project seeks to gain knowledge of how these fundamental phenomena influence the way membrane proteins function as they work to control the movement of molecules and signals in and out of our cells. Such information will be required to understand both the complex web of signaling and energy transduction mechanisms required for normal cellular function and their pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54GM087519-08
Application #
9351521
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Preusch, Peter
Project Start
2010-08-10
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2019-08-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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-Rodríguez, 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