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- PDB-9y1q: Alternative NBD1-binding geometry in channel-formed, ATP-bound, V... -

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Entry
Database: PDB / ID: 9y1q
TitleAlternative NBD1-binding geometry in channel-formed, ATP-bound, VX809-bound, T2a-nanobody-bound wild-type human CFTR (Composite map from PHENIX)
Components
  • Cystic fibrosis transmembrane conductance regulator
  • T2a nanobody
  • UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK
KeywordsMEMBRANE PROTEIN / cystic fibrosis / CFTR / nanobody / protein folding
Function / homology
Function and homology information


Sec61 translocon complex binding / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / positive regulation of enamel mineralization / RHO GTPases regulate CFTR trafficking / transepithelial water transport / intracellular pH elevation / amelogenesis / chloride channel inhibitor activity / multicellular organismal-level water homeostasis ...Sec61 translocon complex binding / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / positive regulation of enamel mineralization / RHO GTPases regulate CFTR trafficking / transepithelial water transport / intracellular pH elevation / amelogenesis / chloride channel inhibitor activity / multicellular organismal-level water homeostasis / water transport / chloride channel regulator activity / Golgi-associated vesicle membrane / bicarbonate transmembrane transporter activity / membrane hyperpolarization / bicarbonate transport / chloride transmembrane transporter activity / sperm capacitation / RHOQ GTPase cycle / chloride channel activity / ATPase-coupled transmembrane transporter activity / chloride channel complex / ABC-type transporter activity / 14-3-3 protein binding / cellular response to cAMP / response to endoplasmic reticulum stress / cellular response to forskolin / chloride transmembrane transport / Developmental Lineage of Pancreatic Ductal Cells / PDZ domain binding / clathrin-coated endocytic vesicle membrane / Late endosomal microautophagy / Defective CFTR causes cystic fibrosis / recycling endosome / ABC-family protein mediated transport / recycling endosome membrane / Chaperone Mediated Autophagy / transmembrane transport / Aggrephagy / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / protein-folding chaperone binding / early endosome membrane / basolateral plasma membrane / early endosome / apical plasma membrane / endosome membrane / Ub-specific processing proteases / lysosomal membrane / endoplasmic reticulum membrane / enzyme binding / cell surface / ATP hydrolysis activity / protein-containing complex / ATP binding / membrane / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / CFTR regulator domain / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / Cystic fibrosis transmembrane conductance regulator / : / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site ...: / CFTR regulator domain / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / Cystic fibrosis transmembrane conductance regulator / : / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / ADENOSINE-5'-TRIPHOSPHATE / CHOLESTEROL / DECANE / DODECANE / HEXANE / MYRISTIC ACID / N-OCTANE / Chem-P5S / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE ...1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / ADENOSINE-5'-TRIPHOSPHATE / CHOLESTEROL / DECANE / DODECANE / HEXANE / MYRISTIC ACID / N-OCTANE / Chem-P5S / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / PALMITIC ACID / PHOSPHATIDYLETHANOLAMINE / Lumacaftor / Cystic fibrosis transmembrane conductance regulator
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.86 Å
AuthorsHunt, J.F. / Paige, A.S. / Govaerts, C.
Funding support United States, 1items
OrganizationGrant numberCountry
Cystic Fibrosis FoundationHUNT13XX0, HUNT18G0, HUNT20G0, 004400G222-Hunt, 007997G224-Hunt, FRANK16XX0, FRANK18G0 United States
CitationJournal: To Be Published
Title: Nanobody-Driven Stabilization Synergistically Rescues F508del-CFTR and Reveals an Alternative Active State of the Channel
Authors: Hunt, F.J. / Paige, A.S. / Cohen, B.M. / Goldberg, P.M. / Wang, C. / Loughlin, B.J. / Kappes, J.C. / Yang, Z. / Jiang, F. / Govaerts, C. / Overtus, M. / Urbatsch, I.L. / Lukacs, G.
History
DepositionAug 30, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 9, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 9, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cystic fibrosis transmembrane conductance regulator
B: T2a nanobody
C: UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)203,33935
Polymers190,0203
Non-polymers13,31932
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

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Protein / Antibody / Protein/peptide , 3 types, 3 molecules ABC

#1: Protein Cystic fibrosis transmembrane conductance regulator / CFTR / ATP-binding cassette sub-family C member 7 / Channel conductance-controlling ATPase / cAMP- ...CFTR / ATP-binding cassette sub-family C member 7 / Channel conductance-controlling ATPase / cAMP-dependent chloride channel


Mass: 172734.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CFTR, ABCC7 / Cell (production host): CHO / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P13569, channel-conductance-controlling ATPase
#2: Antibody T2a nanobody


Mass: 15820.306 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Protein/peptide UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK-UNK


Mass: 1464.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell (production host): CHO / Production host: Cricetulus griseus (Chinese hamster)

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Non-polymers , 15 types, 32 molecules

#4: Chemical ChemComp-AJP / Digitonin


Mass: 1229.312 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C56H92O29 / Comment: detergent*YM
#5: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O
#6: Chemical ChemComp-P5S / O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine / phosphatidyl serine


Mass: 792.075 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C42H82NO10P
#7: Chemical ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


Mass: 790.145 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#8: Chemical ChemComp-3PH / 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / PHOSPHATIDIC ACID


Mass: 704.998 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C39H77O8P
#9: Chemical ChemComp-PTY / PHOSPHATIDYLETHANOLAMINE


Mass: 734.039 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C40H80NO8P / Comment: phospholipid*YM
#10: Chemical
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H32O2
#11: Chemical ChemComp-MYR / MYRISTIC ACID


Mass: 228.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H28O2
#12: Chemical ChemComp-D12 / DODECANE


Mass: 170.335 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C12H26
#13: Chemical ChemComp-D10 / DECANE


Mass: 142.282 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22
#14: Chemical ChemComp-HEX / HEXANE


Mass: 86.175 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H14
#15: Chemical ChemComp-OCT / N-OCTANE


Mass: 114.229 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18
#16: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#17: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#18: Chemical ChemComp-VX8 / Lumacaftor / 3-(6-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-3-methylpyridin-2-yl)benzoic acid / VX-809


Mass: 452.407 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18F2N2O5

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Details

Has ligand of interestN
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
1Wild-type human CFTR solubilized in digitonin and cholesterol-hemisuccinate plus T2a nanobody in the presence of 2 mM MgATPCOMPLEX#1-#30MULTIPLE SOURCES
2Wild type human Cystic Fibrosis Transmembrane Conductance Regulator (hCFTR)ORGANELLE OR CELLULAR COMPONENT#11RECOMBINANT
3T2a nanobodyORGANELLE OR CELLULAR COMPONENT#22NATURAL
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.1883 MDaNO
210.1725 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Lama glama (llama)9844
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Cricetulus griseus (Chinese hamster)10029
32Cricetulus griseus (Chinese hamster)10029CHO
43Cricetulus griseus (Chinese hamster)10029
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1200 mMSodium ChlorideNaCl1
23 mMMagnesium ChlorideMgCl21
350 mMTris bufferC4H11NO31
40.06 % (w/v)DigitoninC56H92O291
52 mMATPC10H16N5O13P31
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: The grid was treated in a Solarus Plasma Cleaner 950 (Gatan Inc., USA) for 25 sec with O2/H2 flow-rates of 27.5/6.4 sccm and 15 W cleaning power.
Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1
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: 105000 X / Nominal defocus max: 2900 nm / Nominal defocus min: 200 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 90 K / Temperature (min): 85 K
Image recordingAverage exposure time: 2.5 sec. / Electron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 11110
Details: Movies comprised 40 frames collected in 2.5 seconds.
EM imaging opticsEnergyfilter name: GIF Quantum ER / Energyfilter slit width: 20 eV
Image scansSampling size: 5 µm / Width: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARC4.3.1particle selectionTemplate picking
2Leginon3.6image acquisition
4cryoSPARC4.3.1CTF correctionPatch CTF correction
10cryoSPARC4.3.1initial Euler assignment
11cryoSPARC4.3.1final Euler assignment
12cryoSPARC4.7.0classification
13cryoSPARC4.7.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2635244
3D reconstructionResolution: 3.86 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36856 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingDetails: Real space refinement in PHENIX using default parameters with separate grouped ADPs for side chain and backbone atoms. REMARK Because of the relatively low resolution and the anisotropy of ...Details: Real space refinement in PHENIX using default parameters with separate grouped ADPs for side chain and backbone atoms. REMARK Because of the relatively low resolution and the anisotropy of the map corresponding to this model, it was built primarily by transferring coordinates from higher resolution structures with equivalent conformations. The model for NBD2, the transmembrane region, and the bound lipids came from a 2.98 A structure of an "NBD1less" conformation of human CFTR that has no significant density for NBD1. The model for NBD1 and T2a came from a 3.04 A structure of the standard "VShaped" conformation of human CFTR (without the internal chloride channel formed) that has the T2a nanobody bound to NBD1. The relevant portions of those two models were aligned with the density in ChimeraX and then combined with a model for the C peptide that was built directly into this map. The C peptide, which has not been assigned to a specific CFTR sequence, likely derives from either the Regulatory Insertion spanning residues 403-436 or the R Region spanning residues 638-840. No manual rebuilding was performed on the model, although a small number of protein segments and two ligands showing stereochemical strains or clashes in an initial refinement in PHENIX were subject to real space refinement in COOT. Occupancy refinement was performed on the two backbone segments that have alternative conformations in the NBD1less model (541-548 and 919-922) and also on residues 1012-1034 in CFTR and the entirety of the T2a nanobody.
RefinementHighest resolution: 3.86 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00410276
ELECTRON MICROSCOPYf_angle_d0.73613853
ELECTRON MICROSCOPYf_dihedral_angle_d13.9961991
ELECTRON MICROSCOPYf_chiral_restr0.0451567
ELECTRON MICROSCOPYf_plane_restr0.0061640

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