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- PDB-9mm5: CGRP Receptor in complex with dC2_049 -

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Basic information

Entry
Database: PDB / ID: 9mm5
TitleCGRP Receptor in complex with dC2_049
Components
  • Calcitonin gene-related peptide type 1 receptor
  • De novo designed minibinder - dC2_049
  • Receptor activity-modifying protein 1
KeywordsMEMBRANE PROTEIN / GPCR / denovo 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 receptor signaling pathway ...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 / calcitonin gene-related peptide receptor activity / positive regulation of glycoprotein biosynthetic process / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / Calcitonin-like ligand receptors / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / cellular response to hormone stimulus / coreceptor activity / regulation of G protein-coupled receptor signaling pathway / protein localization to plasma membrane / receptor internalization / intracellular protein transport / G protein-coupled receptor activity / calcium ion transport / protein transport / angiogenesis / adenylate cyclase-activating G protein-coupled receptor signaling pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (s) signalling events / signaling receptor complex / cell surface receptor signaling pathway / lysosome / 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 speciessynthetic construct (others)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.26 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: Nature / Year: 2026
Title: De novo design of miniproteins targeting GPCRs.
Authors: Edin Muratspahić / David Feldman / David E Kim / Xiangli Qu / Ana-Maria Bratovianu / Paula Rivera-Sánchez / Jan Hendrik Voss / Emil P T Hertz / Mads Jeppesen / Federica Dimitri / Kensuke ...Authors: Edin Muratspahić / David Feldman / David E Kim / Xiangli Qu / Ana-Maria Bratovianu / Paula Rivera-Sánchez / Jan Hendrik Voss / Emil P T Hertz / Mads Jeppesen / Federica Dimitri / Kensuke Sakamoto / Amrita Nallathambi / Pia Peceli / Jianjun Cao / Brian P Cary / Matthew J Belousoff / Peter Keov / Phuc N H Trinh / Qingchao Chen / Yue Ren / Justyn Fine / Sudha Mishra / Annu Dalal / Shachie Sinha / Ramanuj Banerjee / Manisankar Ganguly / Karthik Varappalayam Karuppusamy / Isaac Sappington / Thomas Schlichthaerle / Jason Z Zhang / Arvind Pillai / Brian Coventry / Ljubica Mihaljević / Magnus S 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 / Lukas Deweid / Anja Bennett / Jendrik Schöppe / Tiantang Dong / Xiaoli Yan / Luke Oostdyk / William Cao / Lakshmi Anantharaman / Johan J Weisser / Jesper Frank Bastlund / Christoffer Bundgaard / Ayodeji A Asuni / Justin G English / Lance J Stewart / Lauren Halloran / Jamie B Spangler / André Lieber / Arun K Shukla / Patrick M Sexton / Bryan L Roth / Brian E Krumm / Denise Wootten / Christopher G Tate / Christoffer Norn / David Baker /
Abstract: G-protein-coupled receptors (GPCRs) have key roles in physiology and are central targets for drug discovery and development, but the design of protein agonists and antagonists has been challenging as ...G-protein-coupled receptors (GPCRs) have key roles in physiology and are central targets for drug discovery and development, but the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe de novo design methods and a high-throughput receptor-diversion microscopy-based screen for generating GPCR-binding miniproteins with high affinity, potency and selectivity. We design miniprotein agonists that activate receptors involved in itch and pain, as well as antagonists that inhibit receptors implicated in cancer, metabolic disorders such as diabetes and obesity, and migraines. The cryo-electron microscopy (cryo-EM) structures of five receptor-bound designs are close to the computational design models. A designed chemokine receptor antagonist mobilizes haematopoietic stem and progenitor cells in vivo at a level comparable to a clinically used drug, with fewer adverse effects.
History
DepositionDec 19, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 28, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.0Jan 28, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Aug 12, 2026Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / em_admin / em_imaging
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Revision 1.1Aug 12, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / EM metadata
Group: Data collection / Database references / Experimental summary
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata
Category: citation / citation_author ...citation / citation_author / em_admin / em_imaging
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Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _em_imaging.accelerating_voltage / _em_imaging.microscope_model / _em_imaging.nominal_magnification
Revision 1.2Sep 9, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.2Sep 9, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: De novo designed minibinder - dC2_049
E: Receptor activity-modifying protein 1
R: Calcitonin gene-related peptide type 1 receptor


Theoretical massNumber of molelcules
Total (without water)81,3113
Polymers81,3113
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 De novo designed minibinder - dC2_049


Mass: 7970.083 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)
#2: 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
#3: 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
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: CGRP Receptor in complex with dC2_049 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenConc.: 11 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 20 mA discharge / Grid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 1200 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderSpecimen holder model: OTHER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)
Image scansWidth: 4096 / Height: 4096

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Processing

EM softwareName: PHENIX / Version: 1.19.2_4158 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 175000 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingSource name: RoseTTAFold / Type: in silico model
RefinementHighest resolution: 3.26 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034532
ELECTRON MICROSCOPYf_angle_d0.6636158
ELECTRON MICROSCOPYf_dihedral_angle_d5.037586
ELECTRON MICROSCOPYf_chiral_restr0.04684
ELECTRON MICROSCOPYf_plane_restr0.004760

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