[English] 日本語
![](img/lk-miru.gif)
- PDB-7duq: Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 r... -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 7duq | ||||||
---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 receptor-Gs complex | ||||||
![]() |
| ||||||
![]() | BIOSYNTHETIC PROTEIN / Glucagon-like peptide-1 receptor / Glucagon-like peptide-1 / Ago-allosteric modulator / Type 2 diabetes / Compound 2 / Class B GPCR | ||||||
Function / homology | ![]() glucagon receptor binding / glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of execution phase of apoptosis / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor ...glucagon receptor binding / glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of execution phase of apoptosis / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / post-translational protein targeting to membrane, translocation / feeding behavior / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / alkylglycerophosphoethanolamine phosphodiesterase activity / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / response to psychosocial stress / G alpha (i) signalling events / regulation of heart contraction / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of calcium ion import / cellular response to glucagon stimulus / response to starvation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / regulation of insulin secretion / PKA activation in glucagon signalling / hair follicle placode formation / mu-type opioid receptor binding / photoreceptor outer segment / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Synthesis, secretion, and deacylation of Ghrelin / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of gluconeogenesis / cardiac muscle cell apoptotic process / protein kinase A signaling / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / photoreceptor inner segment / cAMP-mediated signaling / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / response to activity / gluconeogenesis / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cognition / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / platelet aggregation / Glucagon-type ligand receptors Similarity search - Function | ||||||
Biological species | ![]() ![]() ![]() ![]() ![]() synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å | ||||||
![]() | Cong, Z. / Chen, L. / Ma, H. / Zhou, Q. / Zou, X. / Ye, C. / Dai, A. / Liu, Q. / Huang, W. / Sun, X. ...Cong, Z. / Chen, L. / Ma, H. / Zhou, Q. / Zou, X. / Ye, C. / Dai, A. / Liu, Q. / Huang, W. / Sun, X. / Wang, X. / Xu, P. / Zhao, L. / Xia, T. / Zhong, W. / Yang, D. / Xu, H.E. / Zhang, Y. / Wang, M. | ||||||
![]() | ![]() Title: Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. Authors: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong ...Authors: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang / ![]() Abstract: The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy ...The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics. | ||||||
History |
|
-
Structure visualization
Movie |
![]() |
---|---|
Structure viewer | Molecule: ![]() ![]() |
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 225 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 181.2 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 39.2 KB | Display | |
Data in CIF | ![]() | 58.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 30866MC ![]() 7durC ![]() 7e14C ![]() 7evmC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
-Glucagon-like peptide ... , 2 types, 2 molecules PR
#1: Protein/peptide | Mass: 3302.648 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) ![]() |
---|---|
#2: Protein | Mass: 50860.801 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#3: Protein | Mass: 45683.434 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
---|---|
#4: Protein | Mass: 37915.496 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
#5: Protein | Mass: 7729.947 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
-Antibody , 1 types, 1 molecules N
#6: Antibody | Mass: 15343.019 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) |
---|
-Non-polymers , 2 types, 8 molecules ![](data/chem/img/HNO.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/CLR.gif)
#7: Chemical | ChemComp-HNO / |
---|---|
#8: Chemical | ChemComp-CLR / |
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-
Sample preparation
Component |
| ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Molecular weight | Units: MEGADALTONS / Experimental value: YES | ||||||||||||||||||||||||||||||||||||
Source (natural) |
| ||||||||||||||||||||||||||||||||||||
Source (recombinant) |
| ||||||||||||||||||||||||||||||||||||
Buffer solution | pH: 7.4 | ||||||||||||||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 80 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k) |
-
Processing
Software | Name: PHENIX / Version: 1.16_3549: / Classification: refinement | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 614978 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
|