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- EMDB-68747: Structure of CXCR4 in complex with a de-novo designed mini-protei... -

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Basic information

Entry
Database: EMDB / ID: EMD-68747
TitleStructure of CXCR4 in complex with a de-novo designed mini-protein antagonist
Map data
Sample
  • Complex: C-X-C chemokine receptor type 4 in complex with dCX001
    • Complex: C-X-C chemokine receptor type 4 / CXCR4
      • Protein or peptide: C-X-C chemokine receptor type 4
    • Complex: dCX001 binder antagonist
      • Protein or peptide: dCX001 binder antagonist
  • Ligand: CHOLESTEROL
  • Ligand: (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate
KeywordsGPCR / G protein / SIGNALING 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
C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.28 Å
AuthorsBanerjee R / Ganguly M / Banerjee N / Tiwari D / Muratspahic E / Baker D / Shukla AK
Funding support India, United Kingdom, 3 items
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, 2026-
Header (metadata) releaseApr 22, 2026-
Map releaseApr 22, 2026-
UpdateJun 3, 2026-
Current statusJun 3, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_68747.png

Downloads & links

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Map

FileDownload / File: emd_68747.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.94 Å/pix.
x 288 pix.
= 271.359 Å		0.94 Å/pix.
x 288 pix.
= 271.359 Å		0.94 Å/pix.
x 288 pix.
= 271.359 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.94222 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.120801084 - 1.2735469
Average (Standard dev.)0.017532445 (±0.017906358)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 271.35934 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_68747_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_68747_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : C-X-C chemokine receptor type 4 in complex with dCX001

EntireName: C-X-C chemokine receptor type 4 in complex with dCX001
Components
  • Complex: C-X-C chemokine receptor type 4 in complex with dCX001
    • Complex: C-X-C chemokine receptor type 4 / CXCR4
      • Protein or peptide: C-X-C chemokine receptor type 4
    • Complex: dCX001 binder antagonist
      • Protein or peptide: dCX001 binder antagonist
  • Ligand: CHOLESTEROL
  • Ligand: (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate

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Supramolecule #1: C-X-C chemokine receptor type 4 in complex with dCX001

SupramoleculeName: C-X-C chemokine receptor type 4 in complex with dCX001
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: C-X-C chemokine receptor type 4 / CXCR4

SupramoleculeName: C-X-C chemokine receptor type 4 / CXCR4 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2

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Supramolecule #3: dCX001 binder antagonist

SupramoleculeName: dCX001 binder antagonist / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1

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Macromolecule #1: dCX001 binder antagonist

MacromoleculeName: dCX001 binder antagonist / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 9.994729 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MSGMVLKAVS MPTGIYSKLK KEYGEEIEKK AKELGVKISY GYRNGEMLIG FSGKKEEVDK LVKYVKKIVT EISRKRNGSL EHHHHHH

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Macromolecule #2: C-X-C chemokine receptor type 4

MacromoleculeName: C-X-C chemokine receptor type 4 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.688859 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGKTIIALSY IFCLVFADYK DDDDAANFTP VNGSSGNQSV RLVTSSSLEV LFQGPGSEGI SIYTSDNYTE EMGSGDYDSM KEPCFREEN ANFNKIFLPT IYSIIFLTGI VGNGLVILVM GYQKKLRSMT DKYRLHLSVA DLLFVITLPF WAVDAVANWY F GNFLCKAV ...String:
MGKTIIALSY IFCLVFADYK DDDDAANFTP VNGSSGNQSV RLVTSSSLEV LFQGPGSEGI SIYTSDNYTE EMGSGDYDSM KEPCFREEN ANFNKIFLPT IYSIIFLTGI VGNGLVILVM GYQKKLRSMT DKYRLHLSVA DLLFVITLPF WAVDAVANWY F GNFLCKAV HVIYTVNLYS SVLILAFISL DRYLAIVHAT NSQRPRKLLA EKVVYVGVWI PALLLTIPDF IFANVSEADD RY ICDRFYP NDLWVVVFQF QHIMVGLILP GIVILSCYCI IISKLSHSKG HQKRKALKTT VILILAFFAC WLPYYIGISI DSF ILLEII KQGCEFENTV HKWISITEAL AFFHCCLNPI LYAFLGAKFK TSAQHALTSV SRGSSLKILS KGKRGGHSSV STES ESSSF HSS

UniProtKB: C-X-C chemokine receptor type 4

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec...

MacromoleculeName: (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate
type: ligand / ID: 4 / Number of copies: 3 / Formula: D21
Molecular weightTheoretical: 674.929 Da
Chemical component information

ChemComp-D21:
(2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Average electron dose: 75.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8u4s

Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 18396
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

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

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