Contents

Abstract 228

11.1 Introduction 228

11.2 Structure, Stability, Dynamics and Conformational Changes of Rhodopsin 230

11.2.1 Early Magnetic Resonance Studies of Chromophore and Protein-Lipid Interactions 230

11.2.2 Advent of Recombinant Expression and Purification Technology 231

11.2.3 Rhodopsin Structure via Cysteine Mutagenesis Followed by Biochemical and Biophysical Analyses 232

11.2.3.1 Cysteine Reactivity as Qualitative Indicator for Structure 233

11.2.3.2 Distance Constraints by Rates of Disulfide Bond Formation 235

11.2.3.3 Mobility, Accessibility, and Distance Constraints via Electron Paramagnetic Resonance Spectroscopy 235

11.2.4 Solid-State Nuclear Magnetic Resonance Applications to Rhodopsin 237

11.2.4.1 Chromophore Structure and Schiff Base Linkage 237

11.2.4.2 Other Tertiary Interactions 238

11.2.5 Solution NMR 239

11.2.5.1 Protein-Protein Interactions 240

11.2.5.2 Rhodopsin Structure 241

11.2.5.3 Conformational Dynamics in Rhodopsin 242

11.2.6 Crystal Structure and Stability of Dark State Rhodopsin 244

11.3 Structures, Dynamics, and Conformational Changes of GPCRs 246

11.3.1 Homology Modeling and GPCR Fragment Studies 246

11.3.2 Structure and Dynamics of Ligands in Context of Full-Length Receptors 248

11.3.3 Conformational Changes

11.3.4 Constraints Locking Receptors in Their Inactive

Conformations

11.3.5 Consequences of Conformational Changes for

GPCR Function

251 251

11.4 Conclusions Acknowledgments.. References

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