Structure of the full-length glucagon class B G-protein-coupled receptor

Nature
Haonan ZhangBeili Wu

Abstract

The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.

References

May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Aug 25, 2004·Proceedings of the National Academy of Sciences of the United States of America·Christy R R GraceRoland Riek
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Apr 3, 2008·Nature Reviews. Drug Discovery·Malin C Lagerström, Helgi B Schiöth
Sep 20, 2008·The Journal of Biological Chemistry·Augen A PioszakH Eric Xu
Dec 3, 2008·Cell Metabolism·Christine LonguetDaniel J Drucker
Apr 25, 2009·Nature Protocols·Martin Caffrey, Vadim Cherezov
May 19, 2009·Trends in Biochemical Sciences·Christoph ParthierMilton T Stubbs
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
May 26, 2010·The Journal of Physical Chemistry. B·Jeffery B KlaudaRichard W Pastor
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·T Geoff G BattyeAndrew G W Leslie
Sep 17, 2011·Journal of Chemical Information and Modeling·Roman A Laskowski, Mark B Swindells
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Pavel V AfoninePaul D Adams
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Oliver S SmartGérard Bricogne
Jun 14, 2012·Journal of the American Society for Mass Spectrometry·Bruce D PascalPatrick R Griffin
Aug 22, 2012·Proceedings of the National Academy of Sciences of the United States of America·Christopher M KothBernard B Allan
Mar 13, 2013·Proceedings of the National Academy of Sciences of the United States of America·Denise WoottenPatrick M Sexton
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Thomas A WhiteHenry N Chapman
Jul 19, 2013·Nature·Fai Yiu SiuRaymond C Stevens
Jul 19, 2013·Nature·Kaspar HollensteinFiona H Marshall
Dec 24, 2013·Trends in Pharmacological Sciences·Kaspar HollensteinRaymond C Stevens
Feb 15, 2014·Nature Communications·Uwe WeierstallVadim Cherezov
May 2, 2015·Journal of Synchrotron Radiation·Mengning LiangSébastien Boutet
Aug 1, 2015·Nature Communications·Linlin YangHualiang Jiang
Apr 26, 2016·Nature·Ali JazayeriFiona H Marshall
Jul 21, 2016·Nature·Eamon F X ByrneChristian Siebold

❮ Previous
Next ❯

Citations

Dec 30, 2017·Science China. Life Sciences·Binghe Tan, Mingyao Liu
Nov 28, 2017·PloS One·Jackelyn MurrayRalph A Tripp
Jul 4, 2018·Acta Crystallographica. Section D, Structural Biology·Ronald E Stenkamp
Aug 4, 2018·Journal of Molecular Neuroscience : MN·Chenyi LiaoJianing Li
Nov 10, 2018·Nature Reviews. Drug Discovery·Ichio ShimadaKurt Wüthrich
Jan 17, 2019·PloS One·Dorota LatekJudyta Cielecka-Piontek
Mar 2, 2019·Acta Crystallographica. Section D, Structural Biology·Marie Luise Grünbein, Gabriela Nass Kovacs
Aug 27, 2017·Diabetes, Obesity & Metabolism·Derek J Nunez, David D'Alessio
May 28, 2019·Journal of Computer-aided Molecular Design·Lee H WinkAbby L Parrill
Jun 12, 2019·Expert Opinion on Drug Discovery·Alexey MishinVadim Cherezov
Aug 17, 2018·Molecular Pharmacology·Xushan WangRobert F Bruns
Jan 10, 2020·Nature·Peishen ZhaoDenise Wootten
Jan 26, 2020·International Journal of Molecular Sciences·Qi KangMingyu Li
Jun 11, 2019·Diabetes·Brian FinanJonathan E Campbell
May 7, 2020·The Journal of Biological Chemistry·Rulue ChangPatrick M Sexton
Apr 9, 2020·Expert Opinion on Biological Therapy·Catherine J Hutchings
Nov 2, 2019·The FEBS Journal·Janosch EhrenmannAndreas Plückthun
Aug 18, 2018·The Journal of Experimental Medicine·Duncan I MackieKathleen M Caron
Aug 24, 2017·Angewandte Chemie·Felix Hausch
Oct 3, 2018·Science China. Life Sciences
Dec 5, 2018·Nature Chemical Biology·Yosuke ToyodaTakuya Kobayashi
Aug 28, 2019·Annual Review of Pharmacology and Toxicology·Denise Wootten, Laurence J Miller
Jul 10, 2019·Current Topics in Medicinal Chemistry·Chenyi LiaoJianing Li
Jul 6, 2018·Nature·David M ThalArthur Christopoulos
Aug 15, 2018·Nature Reviews. Molecular Cell Biology·Denise WoottenPatrick M Sexton
Nov 21, 2018·Nature Structural & Molecular Biology·Janosch EhrenmannAndreas Plückthun
Apr 21, 2020·Physical Chemistry Chemical Physics : PCCP·Dali WangChen Song
Jul 1, 2020·Biochemical Society Transactions·Andy M LauArgyris Politis
Jun 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Giulio MattediFrancesco Luigi Gervasio
Mar 11, 2020·Nature Communications·Fan WuRaymond C Stevens
Jun 3, 2018·Hormones : International Journal of Endocrinology and Metabolism·Vlasios KarageorgosGeorge Liapakis
Jun 24, 2018·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Roger B DoddDarren J Schofield

❮ Previous
Next ❯

Methods Mentioned

BETA
cross-linking studies
X-ray
transfection
size-exclusion chromatography
FRET
flow cytometry

Software Mentioned

MolProbity
Phenix Xtriage
DirAx
Coot
CrystFEL
Mascot
HDX Workbench
BUSTER
REFMAC
MOSFLM

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.