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- PDB-8vlx: HTT in complex with HAP40 and a small molecule. -

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Basic information

Entry
Database: PDB / ID: 8vlx
TitleHTT in complex with HAP40 and a small molecule.
Components
  • 40-kDa huntingtin-associated protein
  • Huntingtin
KeywordsUNKNOWN FUNCTION / Huntington's Disease / neurodegenerative disease
Function / homology
Function and homology information


vesicle cytoskeletal trafficking / regulation of cAMP-dependent protein kinase activity / regulation of phosphoprotein phosphatase activity / positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / microtubule-based transport / vocal learning / regulation of CAMKK-AMPK signaling cascade / negative regulation of proteasomal protein catabolic process / positive regulation of mitophagy / profilin binding ...vesicle cytoskeletal trafficking / regulation of cAMP-dependent protein kinase activity / regulation of phosphoprotein phosphatase activity / positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / microtubule-based transport / vocal learning / regulation of CAMKK-AMPK signaling cascade / negative regulation of proteasomal protein catabolic process / positive regulation of mitophagy / profilin binding / vesicle transport along microtubule / positive regulation of cilium assembly / presynaptic cytosol / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / positive regulation of aggrephagy / postsynaptic cytosol / positive regulation of lipophagy / dynein intermediate chain binding / beta-tubulin binding / Golgi organization / establishment of mitotic spindle orientation / dynactin binding / Regulation of MECP2 expression and activity / autophagosome / inclusion body / heat shock protein binding / centriole / negative regulation of extrinsic apoptotic signaling pathway / protein destabilization / cytoplasmic vesicle membrane / kinase binding / p53 binding / late endosome / transmembrane transporter binding / early endosome / nuclear body / positive regulation of apoptotic process / axon / apoptotic process / dendrite / perinuclear region of cytoplasm / Golgi apparatus / endoplasmic reticulum / protein-containing complex / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Factor VIII intron 22 protein / Huntingtin / Huntingtin, middle-repeat / Huntingtin family / : / : / : / Huntingtin, N-terminal HEAT / Huntingtin, bridge / Huntingtin, N-terminal HEAT 1 ...Factor VIII intron 22 protein / Huntingtin / Huntingtin, middle-repeat / Huntingtin family / : / : / : / Huntingtin, N-terminal HEAT / Huntingtin, bridge / Huntingtin, N-terminal HEAT 1 / Huntingtin, C-terminal HEAT / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / Armadillo-type fold
Similarity search - Domain/homology
: / 40-kDa huntingtin-associated protein / Huntingtin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsPoweleit, N. / Boudet, J. / Doherty, E.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: To Be Published
Title: Discovery of a Small Molecule Ligand to the Huntingtin/HAP40 complex
Authors: Poweleit, N. / Boudet, J. / Doherty, E.
History
DepositionJan 12, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Structure summary / Category: struct_keywords
Item: _struct_keywords.pdbx_keywords / _struct_keywords.text

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Huntingtin
B: 40-kDa huntingtin-associated protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)395,2423
Polymers394,8362
Non-polymers4071
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Huntingtin / / Huntington disease protein / HD protein


Mass: 353493.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTT, HD, IT15 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P42858
#2: Protein 40-kDa huntingtin-associated protein / HAP40 / CpG island protein / Factor VIII intron 22 protein


Mass: 41342.254 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F8A1, F8A2, F8A3 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P23610
#3: Chemical ChemComp-A1ACS / N-[(1S,2R)-2-benzylcyclopentyl]-N'-{1-[(1S)-1-(pyridin-4-yl)ethyl]piperidin-4-yl}urea


Mass: 406.564 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34N4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: HTT and HAP40 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
Buffer solutionpH: 7.4
Details: 25 mM Hepes, 300 mM NaCl, 0.025%CHAPS, 1mM DTT, 1mM Ligand, 1% DMSO
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GRAPHENE OXIDE / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 4 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: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 1.4 sec. / Electron dose: 50.48 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6788

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.2particle selection
2Leginonimage acquisition
4cryoSPARC4.2CTF correction
7UCSF ChimeraXmodel fitting
9cryoSPARC4.2initial Euler assignment
10cryoSPARC4.2final Euler assignment
11cryoSPARC4.2classification
12cryoSPARC4.23D reconstruction
13Cootmodel refinement
14PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6600000
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 466629 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model

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