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- PDB-6xe6: Structure of Human Dispatched-1 (DISP1) -

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Basic information

Entry
Database: PDB / ID: 6xe6
TitleStructure of Human Dispatched-1 (DISP1)
ComponentsProtein dispatched homolog 1
KeywordsMEMBRANE PROTEIN / hedgehog / secretion / sterol binding / Sterol-sensing domain
Function / homology
Function and homology information


patched ligand maturation / diaphragm development / embryonic pattern specification / peptide transmembrane transporter activity / dorsal/ventral pattern formation / determination of left/right symmetry / peptide transport / smoothened signaling pathway / regulation of protein secretion / protein homotrimerization ...patched ligand maturation / diaphragm development / embryonic pattern specification / peptide transmembrane transporter activity / dorsal/ventral pattern formation / determination of left/right symmetry / peptide transport / smoothened signaling pathway / regulation of protein secretion / protein homotrimerization / basolateral plasma membrane / membrane
Similarity search - Function
: / Protein patched/dispatched / Patched family / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain
Similarity search - Domain/homology
CHOLESTEROL HEMISUCCINATE / Protein dispatched homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.53 Å
AuthorsChen, H. / Liu, Y. / Li, X.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL020948 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM135343 United States
CitationJournal: Life Sci Alliance / Year: 2020
Title: Structure of human Dispatched-1 provides insights into Hedgehog ligand biogenesis.
Authors: Hongwen Chen / Yang Liu / Xiaochun Li /
Abstract: Hedgehog (HH) signaling is essential for metazoan development. The HH ligand is secreted into the extracellular space by a cell surface protein named Dispatched-1 (DISP1). Here, we report the cryo-EM ...Hedgehog (HH) signaling is essential for metazoan development. The HH ligand is secreted into the extracellular space by a cell surface protein named Dispatched-1 (DISP1). Here, we report the cryo-EM structure of human DISP1 protein. DISP1 contains 12 transmembrane helices (TMs) and two extracellular domains (ECDs). Its ECDs reveal an open state, in contrast to its structural homologues PTCH1 and NPC1, whose extracellular/luminal domains adopt a closed state. The low-resolution structure of the DISP1 complex with dual lipid-modified HH ligand reveals how the ECDs of DISP1 engage with HH ligand. Moreover, several cholesterol-like molecules are found in the TMs, implying a transport-like function of DISP1.
History
DepositionJun 12, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_site / struct_site_gen
Item: _chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.2Jan 20, 2021Group: Database references / Structure summary / Category: chem_comp / citation / citation_author
Item: _chem_comp.pdbx_synonyms / _citation.country ..._chem_comp.pdbx_synonyms / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
A: Protein dispatched homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,1547
Polymers124,4991
Non-polymers2,6556
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Protein dispatched homolog 1


Mass: 124498.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DISP1, DISPA / Cell (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q96F81
#2: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C31H50O4
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN

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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: Human dispatched-1 in complex with dual-lipidated SHH-N
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightUnits: MEGADALTONS / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293S GnTI- / Plasmid: pEG BacMam
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMsodium chlorideNaCl1
30.06 %digitoninC56H92O291
40.002 %Cholesteryl Hemisuccinate Tris SaltC31H50O41
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Chamber temperature: 293 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DARK FIELD
Image recordingElectron dose: 62 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0135 / Classification: refinement
EM softwareName: RELION / Category: classification
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 4.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 400432 / Num. of class averages: 2 / Symmetry type: POINT
RefinementResolution: 4.54→213.25 Å / Cor.coef. Fo:Fc: 0.736 / SU B: 72.333 / SU ML: 0.879 / ESU R: 0.39 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.46296 --
obs0.46296 216926 100 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 130.005 Å2
Baniso -1Baniso -2Baniso -3
1--3.4 Å2-1.2 Å22.04 Å2
2---0.54 Å20.86 Å2
3---3.94 Å2
Refinement stepCycle: 1 / Total: 6565
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.010.0196737
ELECTRON MICROSCOPYr_bond_other_d0.0050.026487
ELECTRON MICROSCOPYr_angle_refined_deg1.2921.9759192
ELECTRON MICROSCOPYr_angle_other_deg1.058314884
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.4865815
ELECTRON MICROSCOPYr_dihedral_angle_2_deg34.70823.452252
ELECTRON MICROSCOPYr_dihedral_angle_3_deg16.213151024
ELECTRON MICROSCOPYr_dihedral_angle_4_deg10.0711522
ELECTRON MICROSCOPYr_chiral_restr0.0690.21084
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.027332
ELECTRON MICROSCOPYr_gen_planes_other0.0020.021542
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it2.13313.0953293
ELECTRON MICROSCOPYr_mcbond_other2.13313.0963292
ELECTRON MICROSCOPYr_mcangle_it3.95619.6234097
ELECTRON MICROSCOPYr_mcangle_other3.95619.6234098
ELECTRON MICROSCOPYr_scbond_it1.313.2413444
ELECTRON MICROSCOPYr_scbond_other1.313.2423445
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other2.65219.8175096
ELECTRON MICROSCOPYr_long_range_B_refined8.9238385
ELECTRON MICROSCOPYr_long_range_B_other8.9228386
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 4.54→4.658 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rwork0.562 15963 -
Rfree-0 -
obs--100 %

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