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Yorodumi- EMDB-43877: Human Amylin1 Receptor in Complex with Gs and human Calcitonin Ge... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-43877 | |||||||||||||||
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Title | Human Amylin1 Receptor in Complex with Gs and human Calcitonin Gene-Related Peptide | |||||||||||||||
Map data | postprocess consensus map | |||||||||||||||
Sample |
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Keywords | Amylin receptor / GPCR / RAMP3 / Calcitonin Gene-Related Peptide / MEMBRANE PROTEIN | |||||||||||||||
Function / homology | Function and homology information nervous system process involved in regulation of systemic arterial blood pressure / 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 ...nervous system process involved in regulation of systemic arterial blood pressure / 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 / endothelial cell proliferation / negative regulation of bone resorption / 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 / developmental growth / D1 dopamine receptor binding / endothelial cell migration / intracellular transport / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / coreceptor activity / positive regulation of calcium-mediated signaling / 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 / protein localization to plasma membrane / positive regulation of interleukin-8 production / intracellular protein transport / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / cilium / Prostacyclin signalling through prostacyclin receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / hormone activity / receptor internalization / 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 / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / cognition / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / regulation of blood pressure / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / vasodilation / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) / Lama glama (llama) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.4 Å | |||||||||||||||
Authors | Cao J / Belousoff MJ / Wootten DL / Sexton PM | |||||||||||||||
Funding support | Australia, Japan, 4 items
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Citation | Journal: Biochemistry / Year: 2024 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 | emd_43877.map.gz | 166.1 MB | EMDB map data format | |
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Header (meta data) | emd-43877-v30.xml emd-43877.xml | 38.7 KB 38.7 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_43877_fsc.xml | 12.8 KB | Display | FSC data file |
Images | emd_43877.png | 18.3 KB | ||
Masks | emd_43877_msk_1.map | 178 MB | Mask map | |
Filedesc metadata | emd-43877.cif.gz | 7.8 KB | ||
Others | emd_43877_additional_1.map.gz emd_43877_additional_2.map.gz emd_43877_additional_3.map.gz emd_43877_additional_4.map.gz emd_43877_additional_5.map.gz emd_43877_additional_6.map.gz emd_43877_additional_7.map.gz emd_43877_half_map_1.map.gz emd_43877_half_map_2.map.gz | 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 | http://ftp.pdbj.org/pub/emdb/structures/EMD-43877 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-43877 | HTTPS FTP |
-Related structure data
Related structure data | 9aucMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_43877.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | postprocess consensus map | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
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
-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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Processing | single particle reconstruction |
Aggregation state | particle |
-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 |
-Electron microscopy
Microscope | TFS KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm |
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 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
-Atomic model buiding 1
Refinement | Overall B value: 41 |
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Output model | PDB-9auc: |