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- EMDB-43877: Human Amylin1 Receptor in Complex with Gs and human Calcitonin Ge... -
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Basic information
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Title | Human Amylin1 Receptor in Complex with Gs and human Calcitonin Gene-Related Peptide | |||||||||||||||
![]() | postprocess consensus map | |||||||||||||||
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![]() | Amylin receptor / GPCR / RAMP3 / Calcitonin Gene-Related Peptide / MEMBRANE PROTEIN | |||||||||||||||
Function / homology | ![]() nervous system process involved in regulation of systemic arterial blood pressure / calcitonin receptor binding / calcitonin gene-related peptide binding / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / calcitonin binding / amylin receptor complex 1 / amylin receptor complex 2 / positive regulation of protein glycosylation / cross-receptor inhibition within G protein-coupled receptor heterodimer ...nervous system process involved in regulation of systemic arterial blood pressure / calcitonin receptor binding / calcitonin gene-related peptide binding / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / calcitonin binding / amylin receptor complex 1 / amylin receptor complex 2 / positive regulation of protein glycosylation / cross-receptor inhibition within G protein-coupled receptor heterodimer / amylin receptor complex 3 / amylin receptor activity / calcitonin receptor activity / positive regulation of interleukin-1 alpha production / calcitonin gene-related peptide receptor activity / amylin receptor signaling pathway / positive regulation of adenylate cyclase activity / Calcitonin-like ligand receptors / negative regulation of calcium ion transport into cytosol / positive regulation of macrophage differentiation / regulation of G protein-coupled receptor signaling pathway / G protein-coupled receptor internalization / vasculature development / negative regulation of ossification / negative regulation of bone resorption / endothelial cell proliferation / leukocyte cell-cell adhesion / negative regulation of osteoclast differentiation / positive regulation of protein kinase A signaling / PKA activation in glucagon signalling / response to amyloid-beta / hair follicle placode formation / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / endothelial cell migration / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state / coreceptor activity / positive regulation of calcium-mediated signaling / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / response to glucocorticoid / cellular response to hormone stimulus / regulation of mRNA stability / regulation of cytosolic calcium ion concentration / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / ossification / osteoclast differentiation / acrosomal vesicle / trans-Golgi network membrane / positive regulation of interleukin-8 production / protein localization to plasma membrane / intracellular protein transport / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / bone development / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / hormone activity / receptor internalization / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / cilium / regulation of blood pressure / platelet aggregation / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / vasodilation / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling Similarity search - Function | |||||||||||||||
Biological species | ![]() ![]() ![]() | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.4 Å | |||||||||||||||
![]() | Cao J / Belousoff MJ / Wootten DL / Sexton PM | |||||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP and Gs Protein. Authors: Jianjun Cao / Matthew J Belousoff / Radostin Danev / Arthur Christopoulos / Denise Wootten / Patrick M Sexton / ![]() ![]() Abstract: Inhibition of calcitonin gene-related peptide (CGRP) or its cognate CGRP receptor (CGRPR) has arisen as a major breakthrough in the treatment of migraine. However, a second CGRP-responsive receptor ...Inhibition of calcitonin gene-related peptide (CGRP) or its cognate CGRP receptor (CGRPR) has arisen as a major breakthrough in the treatment of migraine. However, a second CGRP-responsive receptor exists, the amylin (Amy) 1 receptor (AMYR), yet its involvement in the pathology of migraine is poorly understood. AMYR and CGRPR are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with the calcitonin receptor (CTR) and the calcitonin receptor-like receptor (CLR), respectively. Here, we present the structure of AMYR in complex with CGRP and Gs protein and compare it with the reported structures of the AMYR complex with rat amylin (rAmy) and the CGRPR in complex with CGRP. Despite similar protein backbones observed within the receptors and the N- and C-termini of the two peptides bound to the AMYR complexes, they have distinct organization in the peptide midregions (the bypass motif) that is correlated with differences in the dynamics of the respective receptor extracellular domains. Moreover, divergent conformations of extracellular loop (ECL) 3, intracellular loop (ICL) 2, and ICL3 within the CTR and CLR protomers are evident when comparing the CGRP bound to the CGRPR and AMYR, which influences the binding mode of CGRP. However, the conserved interactions made by the C-terminus of CGRP to the CGRPR and AMYR are likely to account for cross-reactivity of nonpeptide CGRPR antagonists observed at AMYR, which also extends to other clinically used CGRPR blockers, including antibodies. | |||||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 166.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 38.7 KB 38.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 12.8 KB | Display | ![]() |
Images | ![]() | 18.3 KB | ||
Masks | ![]() | 178 MB | ![]() | |
Filedesc metadata | ![]() | 7.8 KB | ||
Others | ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() | 158.9 MB 152.4 MB 156.3 MB 141.1 MB 156.6 MB 155.6 MB 163.1 MB 141.5 MB 141.5 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 1 MB | Display | ![]() |
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Full document | ![]() | 1 MB | Display | |
Data in XML | ![]() | 19.9 KB | Display | |
Data in CIF | ![]() | 26.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 9aucMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||
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Annotation | postprocess consensus map | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.65 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
+Mask #1
+Additional map: postprocess map of receptor-focused refinement using auto-generated B...
+Additional map: postprocess map from the ECD-focused refinement using B-factor (-15)
+Additional map: sharpened map of receptor-focused refinement using manual input...
+Additional map: unfiltered consensus map
+Additional map: unfiltered map from the receptor-focused refinement
+Additional map: postprocess map from the ECD-focused refinement
+Additional map: postprocess map from the receptorTMD-focused refinement
+Half map: #2
+Half map: #1
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Sample components
+Entire : Human Amylin 1 Receptor in complex with Gs and human calcitonin g...
+Supramolecule #1: Human Amylin 1 Receptor in complex with Gs and human calcitonin g...
+Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: Nanobody 35
+Macromolecule #5: Receptor activity-modifying protein 1
+Macromolecule #6: Calcitonin gene-related peptide 1
+Macromolecule #7: Calcitonin receptor
+Macromolecule #8: PALMITIC ACID
+Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #10: CHOLESTEROL HEMISUCCINATE
+Macromolecule #11: water
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 5.8 mg/mL |
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Buffer | pH: 7.4 |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | TFS KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 7049 / Average exposure time: 16.12 sec. / Average electron dose: 71.15 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Overall B value: 41 |
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Output model | ![]() PDB-9auc: |