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Review
. 2018 May 20;47:377-397.
doi: 10.1146/annurev-biophys-070317-033239. Epub 2018 Mar 15.

Serial Femtosecond Crystallography of G Protein-Coupled Receptors

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Free PMC article
Review

Serial Femtosecond Crystallography of G Protein-Coupled Receptors

Benjamin Stauch et al. Annu Rev Biophys. .
Free PMC article

Abstract

G protein-coupled receptors (GPCRs) represent a large superfamily of membrane proteins that mediate cell signaling and regulate a variety of physiological processes in the human body. Structure-function studies of this superfamily were enabled a decade ago by multiple breakthroughs in technology that included receptor stabilization, crystallization in a membrane environment, and microcrystallography. The recent emergence of X-ray free-electron lasers (XFELs) has further accelerated structural studies of GPCRs and other challenging proteins by overcoming radiation damage and providing access to high-resolution structures and dynamics using micrometer-sized crystals. Here, we summarize key technology advancements and major milestones of GPCR research using XFELs and provide a brief outlook on future developments in the field.

Keywords: G protein–coupled receptor; X-ray free-electron laser; lipidic cubic phase; serial femtosecond crystallography; structure-function.

Figures

Figure 1
Figure 1. GPCR function and pervasiveness of in physiology and pathology.
Physiological systems (bold black) and pathological conditions (bold red) linked to GPCR families (black) are indicated.
Figure 2.
Figure 2.. GPCR structure determination pipeline.
The pipeline contains several feedback loops and readout options (biochemical assays) which allow monitoring project progress, often bringing the process back to initial construct design.
Figure 3.
Figure 3.. SFX-LCP process.
(a) Schematic of an LCP-SFX data collection setup. XFEL beam is focused to a diameter of ~1 μm by a pair of KB mirrors on a stream of LCP delivering micrometer-sized crystals intersecting the beam in random orientations. Diffraction patterns are collected by a CSPAD detector at 120 Hz. (b) Zoom in on the sample interaction region and LCP microstructure. (c) XFEL beam footprints at ~1% intensity (8·109 photons/pulse). (d) XFEL beam at ~50% intensity (4·1011 photons/pulse) creates an explosion of ~100 μm in size.
Figure 4.
Figure 4.. Timeline of GPCR structure determination at XFELs.
Important milestones (top) and determined GPCR structures (bottom) are shown on a timeline.

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