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- PDB-9mni: CGRP Receptor in complex with dC2_050 -

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Basic information

Entry
Database: PDB / ID: 9mni
TitleCGRP Receptor in complex with dC2_050
Components
  • Calcitonin gene-related peptide type 1 receptor
  • De novo designed minibinder - dC2_050
  • Receptor activity-modifying protein 1
KeywordsMEMBRANE PROTEIN / GPCR / de novo protein design
Function / homology
Function and homology information


calcitonin gene-related peptide binding / cellular response to sucrose stimulus / adrenomedullin binding / CGRP receptor complex / : / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity / calcitonin receptor activity ...calcitonin gene-related peptide binding / cellular response to sucrose stimulus / adrenomedullin binding / CGRP receptor complex / : / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity / calcitonin receptor activity / calcitonin gene-related peptide receptor signaling pathway / vascular associated smooth muscle cell proliferation / calcitonin gene-related peptide receptor activity / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / Calcitonin-like ligand receptors / regulation of G protein-coupled receptor signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / cellular response to hormone stimulus / coreceptor activity / positive regulation of vascular associated smooth muscle cell proliferation / protein localization to plasma membrane / intracellular protein transport / G protein-coupled receptor activity / receptor internalization / adenylate cyclase-activating G protein-coupled receptor signaling pathway / calcium ion transport / protein transport / heart development / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / angiogenesis / G alpha (s) signalling events / cell surface receptor signaling pathway / lysosome / receptor complex / endosome / G protein-coupled receptor signaling pathway / cell surface / endoplasmic reticulum / plasma membrane / cytoplasm
Similarity search - Function
GPCR, family 2, calcitonin gene-related peptide, type 1 receptor / Receptor activity modifying protein / RAMP domain superfamily / Receptor activity modifying family / GPCR, family 2, calcitonin receptor family / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors ...GPCR, family 2, calcitonin gene-related peptide, type 1 receptor / Receptor activity modifying protein / RAMP domain superfamily / Receptor activity modifying family / GPCR, family 2, calcitonin receptor family / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2.
Similarity search - Domain/homology
Receptor activity-modifying protein 1 / Calcitonin gene-related peptide type 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.06 Å
AuthorsCao, J. / Cary, B.P. / Belousoff, M.J. / Wootten, D.L.
Funding support Australia, 4items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1150083 Australia
Australian Research Council (ARC)DP210101504 Australia
National Health and Medical Research Council (NHMRC, Australia)2026300 Australia
Australian Research Council (ARC)IC200100052 Australia
CitationJournal: bioRxiv / Year: 2025
Title: design of miniprotein agonists and antagonists targeting G protein-coupled receptors.
Authors: Edin Muratspahić / David Feldman / David E Kim / Xiangli Qu / Ana-Maria Bratovianu / Paula Rivera-Sánchez / Federica Dimitri / Jason Cao / Brian P Cary / Matthew J Belousoff / Peter Keov / ...Authors: Edin Muratspahić / David Feldman / David E Kim / Xiangli Qu / Ana-Maria Bratovianu / Paula Rivera-Sánchez / Federica Dimitri / Jason Cao / Brian P Cary / Matthew J Belousoff / Peter Keov / Qingchao Chen / Yue Ren / Justyn Fine / Isaac Sappington / Thomas Schlichthaerle / Jason Z Zhang / Arvind Pillai / Ljubica Mihaljević / Magnus Bauer / Susana Vázquez Torres / Amir Motmaen / Gyu Rie Lee / Long Tran / Xinru Wang / Inna Goreshnik / Dionne K Vafeados / Justin E Svendsen / Parisa Hosseinzadeh / Nicolai Lindegaard / Matthäus Brandt / Yann Waltenspühl / Kristine Deibler / Luke Oostdyk / William Cao / Lakshmi Anantharaman / Lance Stewart / Lauren Halloran / Jamie B Spangler / Patrick M Sexton / Bryan L Roth / Brian E Krumm / Denise Wootten / Christopher G Tate / Christoffer Norn / David Baker /
Abstract: G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as ...G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational design methods and a high throughput "receptor diversion" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity, and the use of these methods to generate MRGPRX1 agonists and CXCR4, GLP1R, GIPR, GCGR and CGRPR antagonists. Cryo-electron microscopy data reveals atomic-level agreement between designed and experimentally determined structures for CGRPR-bound antagonists and MRGPRX1-bound agonists, confirming precise conformational control of receptor function. Our design and screening approach opens new frontiers in GPCR drug discovery and development.
History
DepositionDec 21, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 22, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: Receptor activity-modifying protein 1
R: Calcitonin gene-related peptide type 1 receptor
A: De novo designed minibinder - dC2_050


Theoretical massNumber of molelcules
Total (without water)81,2343
Polymers81,2343
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Receptor activity-modifying protein 1 / Calcitonin-receptor-like receptor activity-modifying protein 1 / CRLR activity-modifying protein 1


Mass: 17066.701 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAMP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O60894
#2: Protein Calcitonin gene-related peptide type 1 receptor / CGRP type 1 receptor / Calcitonin receptor-like receptor


Mass: 56274.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALCRL, CGRPR / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16602
#3: Protein De novo designed minibinder - dC2_050


Mass: 7892.855 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex of RAMP1, CLR, and de novo minibinder dC2_50 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.08 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenConc.: 6.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 600 nm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 4.89 sec. / Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5887

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2PHENIX1.21.2_5419:model refinement
3EPUimage acquisition
5CTFFIND4.1.14CTF correction
10cryoSPARC4.6.0initial Euler assignment
11cryoSPARC4.6.0final Euler assignment
13cryoSPARC4.6.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4782642
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 482106 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0044386
ELECTRON MICROSCOPYf_angle_d0.7735961
ELECTRON MICROSCOPYf_dihedral_angle_d4.501567
ELECTRON MICROSCOPYf_chiral_restr0.045665
ELECTRON MICROSCOPYf_plane_restr0.006733

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