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New approaches towards the understanding of integral membrane proteins: A structural perspective on G protein‐coupled receptors
Author(s) -
Grisshammer Reinhard
Publication year - 2017
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.3200
Subject(s) - g protein coupled receptor , protein crystallization , membrane protein , integral membrane protein , receptor , nanotechnology , structural biology , biophysics , chemistry , computational biology , crystallization , membrane , biology , materials science , biochemistry , organic chemistry
Abstract Three‐dimensional structure determination of integral membrane proteins has advanced in unprecedented detail our understanding of mechanistic events of how ion channels, transporters, receptors, and enzymes function. This exciting progress required a tremendous amount of methods development, as exemplified here with G protein‐coupled receptors (GPCRs): Optimizing the production of GPCRs in recombinant hosts; increasing the probability of crystal formation using high‐affinity ligands, nanobodies, and minimal G proteins for co‐crystallization, thus stabilizing receptors into one conformation; using the T4 lysozyme technology and other fusion partners to promote crystal contacts; advancing crystallization methods including the development of novel detergents, and miniaturization and automation of the lipidic cubic phase crystallization method; the concept of conformational thermostabilization of GPCRs; and developing microfocus X‐ray synchrotron technologies to analyze small GPCR crystals. However, despite immense progress to explain how GPCRs function, many receptors pose intractable hurdles to structure determination at this time. Three emerging methods, serial femtosecond crystallography, micro electron diffraction, and single particle electron cryo‐microscopy, hold promise to overcome current limitations in structural membrane biology.