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- EMDB-24572: SP6-11 biased agonist bound to active human neurokinin 1 receptor... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-24572 | ||||||||||||||||||||||||||||||||||||
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Title | SP6-11 biased agonist bound to active human neurokinin 1 receptor in complex with miniGs/q70 | ||||||||||||||||||||||||||||||||||||
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Function / homology | ![]() substance P receptor activity / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||||||||||||||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | ||||||||||||||||||||||||||||||||||||
Method | ![]() ![]() | ||||||||||||||||||||||||||||||||||||
![]() | Harris JA / Faust B / Gondin AB / Daemgen MA / Suomivuori CM / Veldhuis NA / Cheng Y / Dror RO / Thal D / Manglik A | ||||||||||||||||||||||||||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Selective G protein signaling driven by substance P-neurokinin receptor dynamics. Authors: Julian A Harris / Bryan Faust / Arisbel B Gondin / Marc André Dämgen / Carl-Mikael Suomivuori / Nicholas A Veldhuis / Yifan Cheng / Ron O Dror / David M Thal / Aashish Manglik / ![]() ![]() Abstract: The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G and G proteins. Neurokinin A also activates NK1R, but leads to ...The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G and G proteins. Neurokinin A also activates NK1R, but leads to selective G signaling. How two stimuli yield distinct G protein signaling at the same G protein-coupled receptor remains unclear. We determined cryogenic-electron microscopy structures of active NK1R bound to SP or the G-biased peptide SP6-11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent G signaling but not G signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6-11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling. | ||||||||||||||||||||||||||||||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 115.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 30.3 KB 30.3 KB | Display Display | ![]() |
Images | ![]() | 50.2 KB | ||
Others | ![]() ![]() ![]() | 116.1 MB 18.4 MB 18.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7rmiMC ![]() 7rmgC ![]() 7rmhC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | |
EM raw data | ![]() Data size: 170.8 Data #1: Particle stack and final .star file for SP-NK1R-miniGs399 reconstruction [picked particles - single frame - processed] Data #2: Particle stack and final .star file for SP6-11-NK1R-miniGsq70 reconstruction [picked particles - single frame - processed] Data #3: Particle stack and final .star file for SP-NK1R-miniGsq70 reconstruction [picked particles - single frame - processed]) |
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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 | Unsharpened map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.835 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: Sharpened map
File | emd_24572_additional_1.map | ||||||||||||
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Annotation | Sharpened map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_24572_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_24572_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
+Entire : Substance P bound to Neurokinin 1 receptor-miniGs/q70 complex
+Supramolecule #1: Substance P bound to Neurokinin 1 receptor-miniGs/q70 complex
+Supramolecule #2: Guanine nucleotide-binding protein G(s)/G(q) subunit alpha hybrid
+Supramolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1/...
+Supramolecule #4: Substance-P receptor
+Supramolecule #5: Substance P 6-11
+Supramolecule #6: Nanobody 35
+Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms sh...
+Macromolecule #2: Substance-P receptor
+Macromolecule #3: Substance P 6-11
+Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #6: Nanobody 35
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average exposure time: 5.9 sec. / Average electron dose: 67.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Particle selection | Number selected: 4135583 |
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CTF correction | Software - Name: cryoSPARC / Software - details: Patch CTF |
Startup model | Type of model: OTHER / Details: From Ab initio reconstruction |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC |
Final 3D classification | Number classes: 4 / Software - Name: RELION |
Final angle assignment | Type: ANGULAR RECONSTITUTION / Software - Name: cisTEM |
Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM / Number images used: 59926 |