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- PDB-22xc: Structure of CXCR4 in complex with a de-novo designed mini-protei... -

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Basic information

Entry
Database: PDB / ID: 22xc
TitleStructure of CXCR4 in complex with a de-novo designed mini-protein antagonist
Components
  • C-X-C chemokine receptor type 4
  • dCX001 binder antagonist
KeywordsSIGNALING PROTEIN / GPCR / G protein / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


C-X-C motif chemokine 12 receptor activity / positive regulation of macrophage migration inhibitory factor signaling pathway / myosin light chain binding / CXCL12-activated CXCR4 signaling pathway / Specification of primordial germ cells / myelin maintenance / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / C-X-C chemokine receptor activity / positive regulation of vasculature development / Signaling by ROBO receptors ...C-X-C motif chemokine 12 receptor activity / positive regulation of macrophage migration inhibitory factor signaling pathway / myosin light chain binding / CXCL12-activated CXCR4 signaling pathway / Specification of primordial germ cells / myelin maintenance / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / C-X-C chemokine receptor activity / positive regulation of vasculature development / Signaling by ROBO receptors / Formation of definitive endoderm / C-C chemokine receptor activity / C-C chemokine binding / anchoring junction / Chemokine receptors bind chemokines / dendritic cell chemotaxis / cellular response to cytokine stimulus / cell leading edge / positive regulation of oligodendrocyte differentiation / Binding and entry of HIV virion / regulation of cell adhesion / coreceptor activity / neurogenesis / cell chemotaxis / ubiquitin binding / calcium-mediated signaling / brain development / G protein-coupled receptor activity / response to virus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / late endosome / positive regulation of cold-induced thermogenesis / virus receptor activity / positive regulation of cytosolic calcium ion concentration / actin binding / cytoplasmic vesicle / G alpha (i) signalling events / response to hypoxia / early endosome / lysosome / immune response / positive regulation of cell migration / G protein-coupled receptor signaling pathway / inflammatory response / external side of plasma membrane / apoptotic process / ubiquitin protein ligase binding / cell surface / protein-containing complex / extracellular exosome / plasma membrane / cytoplasm
Similarity search - Function
CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / Chemokine receptor family / : / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
CHOLESTEROL / Chem-D21 / C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.28 Å
AuthorsBanerjee, R. / Ganguly, M. / Banerjee, N. / Tiwari, D. / Muratspahic, E. / Baker, D. / Shukla, A.K.
Funding support India, United Kingdom, 3items
OrganizationGrant numberCountry
Science and Engineering Research Board (SERB)IPA/2020/000405 India
Wellcome TrustIA/S/20/1/504916 United Kingdom
Science and Engineering Research Board (SERB)CRG/2022/002646 India
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 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 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) play 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) play 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 computational 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 migraine. Cryo-electron microscopy (cryo-EM) structures of five receptor-bound designs are close to the computational design models. A designed chemokine receptor antagonist mobilizes hematopoietic stem and progenitor cells in vivo at a level comparable to a clinically used drug, with fewer adverse effects.
History
DepositionJan 26, 2026Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 22, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 3, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Jun 3, 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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: dCX001 binder antagonist
B: dCX001 binder antagonist
C: C-X-C chemokine receptor type 4
D: dCX001 binder antagonist
G: C-X-C chemokine receptor type 4
R: C-X-C chemokine receptor type 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,23612
Polymers167,0516
Non-polymers3,1856
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 dCX001 binder antagonist


Mass: 9994.729 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#2: Protein C-X-C chemokine receptor type 4 / CXC-R4 / CXCR-4 / FB22 / Fusin / HM89 / LCR1 / Leukocyte-derived seven transmembrane domain ...CXC-R4 / CXCR-4 / FB22 / Fusin / HM89 / LCR1 / Leukocyte-derived seven transmembrane domain receptor / LESTR / Lipopolysaccharide-associated protein 3 / LAP-3 / LPS-associated protein 3 / NPYRL / Stromal cell-derived factor 1 receptor / SDF-1 receptor


Mass: 45688.859 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCR4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P61073
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-D21 / (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate


Mass: 674.929 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C37H71O8P / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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

Component
IDNameTypeEntity IDParent-IDSource
1C-X-C chemokine receptor type 4 in complex with dCX001COMPLEX#1-#20MULTIPLE SOURCES
2C-X-C chemokine receptor type 4 / CXCR4COMPLEX#21RECOMBINANT
3dCX001 binder antagonistCOMPLEX#11RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Homo sapiens (human)9606
31synthetic construct (others)32630
41Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Spodoptera frugiperda (fall armyworm)7108
21Spodoptera frugiperda (fall armyworm)7108
31Escherichia coli (E. coli)562
41Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 75 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k)
Image scansMovie frames/image: 40

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: NONE
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 18396 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
RefinementHighest resolution: 3.28 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038830
ELECTRON MICROSCOPYf_angle_d0.5111944
ELECTRON MICROSCOPYf_dihedral_angle_d12.7141243
ELECTRON MICROSCOPYf_chiral_restr0.0391382
ELECTRON MICROSCOPYf_plane_restr0.0041408

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