Capturing Peptide–GPCR Interactions and Their Dynamics
Abstract
:1. Introduction
2. The Contact Interface
Crosslinking
3. A Ligand’s Perspective
3.1. Solution State NMR for Low-Affinity Ligands
3.2. Solid-State NMR of High-Affinity Ligands
4. A Receptor’s Perspective
4.1. Selection and Specific Labeling of Sites-of-Interest
4.2. NMR: Investigation of Conformational Equilibria
4.3. NMR: Contribution of Fast Side Chains and Segmental Dynamics?
4.4. Electron Paramagnetic Resonance (EPR)
4.5. Fluorescence
4.6. Fourier-Transform Infrared Spectroscopy (FTIR)
4.7. Hydrogen-Deuterium Exchange (HDX) and Hydroxyl Radical Footprinting (HRF)
5. Conclusions and Perspective
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
A | active |
A2AR | adenosine A2A receptor |
APJR | apelin receptor |
AT1R | angiotensin receptor 1 |
Azi | p-azido-phenylalanine |
β2AR | β2 adrenergic receptor |
B1/2R | bradykinin receptor 1/2 |
BNPS-skatole | 3-bromo-3-methyl-2-(2-nitrophenylthio)-3H-indole |
Bpa | p-benzoyl-phenylalanine |
BRET | bioluminescence resonance energy transfer |
BTFA | 3-bromo-1,1,1-trifluoroacetone |
CCR5 | CC chemokine receptor 5 |
CGRP | calcitonin gene-related peptide |
CRF | corticopin-releasing factor |
CRF1/2R | corticopin-releasing factor receptor 1/2 |
CuAAC | copper-catalyzed azide-alkyne cycloaddition |
CXCL12 | CXC chemokine ligand 12 |
CXCR4 | CXC chemokine receptor 4 |
CPMG | Carr-Purcell-Meiboom-Gill (pulse sequence) |
cwEPR | continuous wave EPR |
DDM | n-dodecyl-β-d-maltopyranoside |
DEER | double electron-electron resonance |
ECD | extracellular domain |
ECL | extracellular loop |
EM | electron microscopy |
EPR | electron paramagnetic resonance |
ETB | endothelin B receptor |
FlAsH | fluorescein arsenical hairpin binder |
FRET | fluorescence/Förster resonance energy transfer |
FTIR | Fourier-transform infrared spectroscopy |
GLP-1 | glucagon-like peptide-1 |
GLP1R | glucagon-like peptide-1 receptor |
GLR | glucagon receptor |
GPCR | G protein-coupled receptor |
HDX | hydrogen-deuterium exchange |
HRF | hydroxyl radical footprinting |
I | inactive |
LRET | lanthanoid resonance energy transfer |
MIP1α | macrophage inflammatory protein 1α (=CCL3) |
MS | mass spectrometry |
MTSL | (1-oxyl-2,2,5,5-tetramethyl-pyrroline-3-methyl) methanethiosulfonate |
ncAA | non-canonical amino acid |
NMR | nuclear magnetic resonance |
NOE | nuclear Overhauser effect |
NPY | neuropeptide Y |
NTS1R | neurotensin receptor 1 |
PACAP | pituitary adenylate cyclase-activating peptide |
PAC1R | pituitary adenylate cyclase-activating peptide receptor 1 |
PTH1R | parathyroid hormone receptor 1 |
REDOR | rotational-echo double-resonance |
SAR | structure activity relationship studies |
SDS-PAGE | sodium dodecyl sulfate–polyacrylamide gel electrophoresis |
SDSL | site-directed spin labeling |
SPAAC | strain-promoted azide-alkyne cycloaddition |
STD | saturation transfer difference spectroscopy |
TCS | transferred cross saturation spectroscopy |
TET | 2,2,2-trifluoro-ethanethiol |
TM | transmembrane |
trNOESY | transferred nuclear Overhauser effect spectroscopy |
Uaa | unnatural amino acid |
Ucn | Urocortin |
Y1/2R | neuropeptide Y receptor 1/2 |
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Method | Label | Introduced by | Provides Information About | Comments | Ref. |
---|---|---|---|---|---|
NMR (solution and solid-state) | 13Cε-methionine or other specifically labeled aa: 13C/15N-tryptophane 13Cδ1 isoleucine 15N-valine 13Cζ-tyrosine; 13Cβ-cysteine etc. | residue-specific during biosynthesis (expression medium) | chemical environment/distinct conformational states, exchange rates between different states can be extracted short-range interactions (via cross-polarization in solid-state NMR) | 13Cε-methionine exploits favorable relaxation profile and flexibility of methyl-groups; deuterated background possible; 15N-valine: backbone assignment | [205,206,207,208,209,210] [217,233,234] [175] [236] [319,320] |
13C-(di)methyl-lysine | residue-specific; chemically: reductive methylation of primary amines with 13CH2O | chemical environment/distinct conformational states short-range interactions (participation in salt bridges) | exploits favorable relaxation profile and flexibility of methyl-groups; negative charge of side chain preserved | [209,321] | |
19F | site-specific (1 label) chemically: (single) reactive cysteine plus TET or BTFA | chemical environment/distinct conformational states exchange rates between different states can be extracted short-range interactions (19F-NOE; 19F-31P REDOR) | direct excitation and no background allow straightforward extraction of entropic and enthalpic parameters <8 Å; up to 12 Å; e.g., phosphorylation sites | [174,214,218,223,224,225,226,227,228,229,230] [226] [322] | |
EPR continuous wave pulsed (DEER) | N-O· (nitroxide radical, typically stabilized by proximal dimethyl groups in a pyrrole ring) | site-specific (1 or 2 labels) chemically: reactive cysteines plus MTSL etc. Uaa labeling possible [201,202,203] | chemical environment, dynamics, accessibility (continuous wave) long-range distances (continuous wave, pulsed (DEER)) | nitroxide scanning (SDSL) allows mapping of secondary structure and membrane boundaries, as well as structural transitions spectral broadening in continuous wave EPR 8–25 Å, DEER 20–70 Å | [191,243,244,245,323,324,325] [326,327,328] [173,214,249] |
Fluorescence Spectroscopy FRET/LRET single molecule microscopy/spectroscopy | fluorophores | site-specific (1 or 2 labels) chemically: (single) reactive cysteines bioorthogonal ligation possible, e.g., “click”-chemistry at genetically engineered Azi; FlAsH-tags etc. [198,273] | shift of environment polarity lifetime of (sub)states (fluorescence anisotropy and lifetime) distances (quenching, FRET, LRET) rate of structural transitions (slower than ms) visualization of transient states not significantly populated in equilibrium | nM protein concentration sufficient, applications in living cells possible distance ranges: tryptophane-induced quenching 5–15 Å 20–80 Å with high orientational dependence for FRET, which is overcome by LRET sm fluorescence with environmentally sensitive fluorophores or smFRET | [192,260,261,262] [193,265,266,267] [260,264] [268] [270] [290,291,292,293] [220] |
FTIR | intrinsic C=O bond vibrations N3 (or CN etc.) bond vibrations | label-free by genetic engineering, e.g., p-azido-phenylalanine (Azi) | protonation switches, secondary structure chemical environment (electrostatics)/distinct conformational states | application of difference spectra to extract responsive C=O signals kinetic resolution up to 1 μs bond vibrations in a region free of endogenous signals | [35,295,296,297,298,299] [204,300] |
HDX HRF | (label-free) | in situ exchange proton-deuterium (reversible) in situ reaction hydroxyl-radical (irreversible) | accessibility, secondary structure, temporal resolution up to seconds accessibility, temporal resolution up to ms | Label free, global view on structural alterations Accuracy depends on coverage and resolution of mass spectrometry | [41,305,306,307,308] [41] |
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Kaiser, A.; Coin, I. Capturing Peptide–GPCR Interactions and Their Dynamics. Molecules 2020, 25, 4724. https://doi.org/10.3390/molecules25204724
Kaiser A, Coin I. Capturing Peptide–GPCR Interactions and Their Dynamics. Molecules. 2020; 25(20):4724. https://doi.org/10.3390/molecules25204724
Chicago/Turabian StyleKaiser, Anette, and Irene Coin. 2020. "Capturing Peptide–GPCR Interactions and Their Dynamics" Molecules 25, no. 20: 4724. https://doi.org/10.3390/molecules25204724