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- EMDB-71743: Structure of HTTQ23-HAP40 complex bound to macrocycles HHL1, HD4 ... -

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Basic information

Entry
Database: EMDB / ID: EMD-71743
TitleStructure of HTTQ23-HAP40 complex bound to macrocycles HHL1, HD4 and HL2
Map dataC1 HHL1 HL2 HD4
Sample
  • Complex: HTT Q23 - HAP40 complex with macrocycles HHL1, HD4 and HL2
    • Complex: HTT-HAP40
      • Protein or peptide: 40-kDa huntingtin-associated protein
      • Protein or peptide: Huntingtin
    • Complex: Macrocyclic peptides
      • Protein or peptide: HHL1
      • Protein or peptide: HD4
      • Protein or peptide: HL2
KeywordsHuntingtin / Macrocycles / Polyglutamine expansion / PEPTIDE BINDING PROTEIN
Function / homology
Function and homology information


vesicle cytoskeletal trafficking / positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / positive regulation of CAMKK-AMPK signaling cascade / microtubule-based transport / vocal learning / negative regulation of proteasomal protein catabolic process / positive regulation of mitophagy / regulation of CAMKK-AMPK signaling cascade / profilin binding / positive regulation of cilium assembly ...vesicle cytoskeletal trafficking / positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / positive regulation of CAMKK-AMPK signaling cascade / microtubule-based transport / vocal learning / negative regulation of proteasomal protein catabolic process / positive regulation of mitophagy / regulation of CAMKK-AMPK signaling cascade / profilin binding / positive regulation of cilium assembly / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / vesicle transport along microtubule / positive regulation of aggrephagy / positive regulation of lipophagy / Golgi organization / dynein intermediate chain binding / establishment of mitotic spindle orientation / dynactin binding / phosphoprotein phosphatase activity / Regulation of MECP2 expression and activity / postsynaptic cytosol / beta-tubulin binding / presynaptic cytosol / inclusion body / heat shock protein binding / centriole / autophagosome / cytoplasmic vesicle membrane / negative regulation of extrinsic apoptotic signaling pathway / protein destabilization / 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 / endoplasmic reticulum / Golgi apparatus / 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) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.1 Å
AuthorsBalakrishnan S / Deme J / Lea SM / Harding RJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)Intramural Research Program United States
CitationJournal: Biorxiv / Year: 2025
Title: High-Affinity, Structure-Validated and Selective Macrocyclic Peptide Tools for Chemical Biology Studies of Huntingtin
Authors: Wolf E / Fanti R / Ikenoue T / Deme JC / Balakrishnan S / Keith BA / Alteen MG / Chandrasekaran R / Yadav M / Bhajiawala R / Ackloo S / Feng J / Pouladi MA / Edwards AM / Wilson D / Lea SM / Suga H / Harding RJ
History
DepositionJul 18, 2025-
Header (metadata) releaseAug 20, 2025-
Map releaseAug 20, 2025-
UpdateAug 20, 2025-
Current statusAug 20, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71743.png

Downloads & links

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Map

FileDownload / File: emd_71743.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationC1 HHL1 HL2 HD4
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 512 pix.
= 374.784 Å		0.73 Å/pix.
x 512 pix.
= 374.784 Å		0.73 Å/pix.
x 512 pix.
= 374.784 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.732 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.111
Minimum - Maximum-0.18465853 - 2.3011484
Average (Standard dev.)0.00081893185 (±0.019962596)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 374.784 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: C1 HHL1 HL2 HD4 Half map A

Fileemd_71743_half_map_1.map
AnnotationC1 HHL1 HL2 HD4 Half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: C1 HHL1 HL2 HD4 Half map B

Fileemd_71743_half_map_2.map
AnnotationC1 HHL1 HL2 HD4 Half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : HTT Q23 - HAP40 complex with macrocycles HHL1, HD4 and HL2

EntireName: HTT Q23 - HAP40 complex with macrocycles HHL1, HD4 and HL2
Components
  • Complex: HTT Q23 - HAP40 complex with macrocycles HHL1, HD4 and HL2
    • Complex: HTT-HAP40
      • Protein or peptide: 40-kDa huntingtin-associated protein
      • Protein or peptide: Huntingtin
    • Complex: Macrocyclic peptides
      • Protein or peptide: HHL1
      • Protein or peptide: HD4
      • Protein or peptide: HL2

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Supramolecule #1: HTT Q23 - HAP40 complex with macrocycles HHL1, HD4 and HL2

SupramoleculeName: HTT Q23 - HAP40 complex with macrocycles HHL1, HD4 and HL2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #5, #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 391 KDa

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Supramolecule #2: HTT-HAP40

SupramoleculeName: HTT-HAP40 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #5, #4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Macrocyclic peptides

SupramoleculeName: Macrocyclic peptides / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#3 / Details: Chemically synthesised
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: HHL1

MacromoleculeName: HHL1 / type: protein_or_peptide / ID: 1 / Details: Macrocycle peptide / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 2.131497 KDa
SequenceString:
(ACE)YLIRSSFNW FVFVEVPC(NH2)

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Macromolecule #2: HD4

MacromoleculeName: HD4 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 2.024365 KDa
SequenceString:
(ACE)(DTY)DIWCETNK QTGILVLC(NH2)

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Macromolecule #3: HL2

MacromoleculeName: HL2 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 1.83016 KDa
SequenceString:
(ACE)YTARYLTLG TLHYKC(NH2)

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Macromolecule #4: Huntingtin

MacromoleculeName: Huntingtin / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 349.486375 KDa
Recombinant expressionOrganism: unidentified baculovirus
SequenceString: MATLEKLMKA FESLKSFQQQ QQQQQQQQQQ QQQQQQQQQQ PPPPPPPPPP PQLPQPPPQA QPLLPQPQPP PPPPPPPPGP AVAEEPLHR PKKELSATKK DRVNHCLTIC ENIVAQSVRN SPEFQKLLGI AMELFLLCSD DAESDVRMVA DECLNKVIKA L MDSNLPRL ...String:
MATLEKLMKA FESLKSFQQQ QQQQQQQQQQ QQQQQQQQQQ PPPPPPPPPP PQLPQPPPQA QPLLPQPQPP PPPPPPPPGP AVAEEPLHR PKKELSATKK DRVNHCLTIC ENIVAQSVRN SPEFQKLLGI AMELFLLCSD DAESDVRMVA DECLNKVIKA L MDSNLPRL QLELYKEIKK NGAPRSLRAA LWRFAELAHL VRPQKCRPYL VNLLPCLTRT SKRPEESVQE TLAAAVPKIM AS FGNFAND NEIKVLLKAF IANLKSSSPT IRRTAAGSAV SICQHSRRTQ YFYSWLLNVL LGLLVPVEDE HSTLLILGVL LTL RYLVPL LQQQVKDTSL KGSFGVTRKE MEVSPSAEQL VQVYELTLHH TQHQDHNVVT GALELLQQLF RTPPPELLQT LTAV GGIGQ LTAAKEESGG RSRSGSIVEL IAGGGSSCSP VLSRKQKGKV LLGEEEALED DSESRSDVSS SALTASVKDE ISGEL AASS GVSTPGSAGH DIITEQPRSQ HTLQADSVDL ASCDLTSSAT DGDEEDILSH SSSQVSAVPS DPAMDLNDGT QASSPI SDS SQTTTEGPDS AVTPSDSSEI VLDGTDNQYL GLQIGQPQDE DEEATGILPD EASEAFRNSS MALQQAHLLK NMSHCRQ PS DSSVDKFVLR DEATEPGDQE NKPCRIKGDI GQSTDDDSAP LVHCVRLLSA SFLLTGGKNV LVPDRDVRVS VKALALSC V GAAVALHPES FFSKLYKVPL DTTEYPEEQY VSDILNYIDH GDPQVRGATA ILCGTLICSI LSRSRFHVGD WMGTIRTLT GNTFSLADCI PLLRKTLKDE SSVTCKLACT AVRNCVMSLC SSSYSELGLQ LIIDVLTLRN SSYWLVRTEL LETLAEIDFR LVSFLEAKA ENLHRGAHHY TGLLKLQERV LNNVVIHLLG DEDPRVRHVA AASLIRLVPK LFYKCDQGQA DPVVAVARDQ S SVYLKLLM HETQPPSHFS VSTITRIYRG YNLLPSITDV TMENNLSRVI AAVSHELITS TTRALTFGCC EALCLLSTAF PV CIWSLGW HCGPPLLSAS DESRKSCTVG MATMILTLLS SAWFPLDLSA HQDALILAGN LLAASAPKSL RSSWASEEEA NPA ATKQEE VWPALGDRAL VPMVEQLFSH LLKVINICAH VLDDVAPGPA IKAALPSLTN PPSLSPIRRK GKEKEPGEQA SVPL SPKKG SEASAASRQS DTSGPVTTSK SSSLGSFYHL PSYLKLHDVL KATHANYKVT LDLQNSTEKF GGFLRSALDV LSQIL ELAT LQDIGKCVEE ILGYLKSCFS REPMMATVCV QQLLKTLFGT NLASQFDGLS SNPSKSQGRA QRLGSSSVRP GLYHYC FMA PYTHFTQALA DASLRNMVQA EQENDTSGWF DVLQKVSTQL KTNLTSVTKN RADKNAIHNH IRLFEPLVIK ALKQYTT TT CVQLQKQVLD LLAQLVQLRV NYCLLDSDQV FIGFVLKQFE YIEVGQFRES EAIIPNIFFF LVLLSYERYH SKQIIGIP K IIQLCDGIMA SGRKAVTHAI PALQPIVHDL FVLRGTNKAD AGKELETQKE VVVSMLLRLI QYHQVLEMFI LVLQQCHKE NEDKWKRLSR QIADIILPML AKQQMHIDSH EALGVLNTLF EILAPSSLRP VDMLLRSMFV TPNTMASVST VQLWISGILA ILRVLISQS TEDIVLSRIQ ELSFSPYLIS CTVINRLRDG DSTSTLEEHS EGKQIKNLPE ETFSRFLLQL VGILLEDIVT K QLKVEMSE QQHTFYCQEL GTLLMCLIHI FKSGMFRRIT AAATRLFRSD GCGGSFYTLD SLNLRARSMI TTHPALVLLW CQ ILLLVNH TDYRWWAEVQ QTPKRHSLSS TKLLSPQMSG EEEDSDLAAK LGMCNREIVR RGALILFCDY VCQNLHDSEH LTW LIVNHI QDLISLSHEP PVQDFISAVH RNSAASGLFI QAIQSRCENL STPTMLKKTL QCLEGIHLSQ SGAVLTLYVD RLLC TPFRV LARMVDILAC RRVEMLLAAN LQSSMAQLPM EELNRIQEYL QSSGLAQRHQ RLYSLLDRFR LSTMQDSLSP SPPVS SHPL DGDGHVSLET VSPDKDWYVH LVKSQCWTRS DSALLEGAEL VNRIPAEDMN AFMMNSEFNL SLLAPCLSLG MSEISG GQK SALFEAAREV TLARVSGTVQ QLPAVHHVFQ PELPAEPAAY WSKLNDLFGD AALYQSLPTL ARALAQYLVV VSKLPSH LH LPPEKEKDIV KFVVATLEAL SWHLIHEQIP LSLDLQAGLD CCCLALQLPG LWSVVSSTEF VTHACSLIHC VHFILEAV A VQPGEQLLSP ERRTNTPKAI SEEEEEVDPN TQNPKYITAA CEMVAEMVES LQSVLALGHK RNSGVPAFLT PLLRNIIIS LARLPLVNSY TRVPPLVWKL GWSPKPGGDF GTAFPEIPVE FLQEKEVFKE FIYRINTLGW TSRTQFEETW ATLLGVLVTQ PLVMEQEES PPEEDTERTQ INVLAVQAIT SLVLSAMTVP VAGNPAVSCL EQQPRNKPLK ALDTRFGRKL SIIRGIVEQE I QAMVSKRE NIATHHLYQA WDPVPSLSPA TTGALISHEK LLLQINPERE LGSMSYKLGQ VSIHSVWLGN SITPLREEEW DE EEEEEAD APAPSSPPTS PVNSRKHRAG VDIHSCSQFL LELYSRWILP SSSARRTPAI LISEVVRSLL VVSDLFTERN QFE LMYVTL TELRRVHPSE DEILAQYLVP ATCKAAAVLG MDKAVAEPVS RLLESTLRSS HLPSRVGALH GILYVLECDL LDDT AKQLI PVISDYLLSN LKGIAHCVNI HSQQHVLVMC ATAFYLIENY PLDVGPEFSA SIIQMCGVML SGSEESTPSI IYHCA LRGL ERLLLSEQLS RLDAESLVKL SVDRVNVHSP HRAMAALGLM LTCMYTGKEK VSPGRTSDPN PAAPDSESVI VAMERV SVL FDRIRKGFPC EARVVARILP QFLDDFFPPQ DIMNKVIGEF LSNQQPYPQF MATVVYKVFQ TLHSTGQSSM VRDWVML SL SNFTQRAPVA MATWSLSCFF VSASTSPWVA AILPHVISRM GKLEQVDVNL FCLVATDFYR HQIEEELDRR AFQSVLEV V AAPGSPYHRL LTCLRNVHKV TTCGGSGDYK DDDDK

UniProtKB: Huntingtin

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Macromolecule #5: 40-kDa huntingtin-associated protein

MacromoleculeName: 40-kDa huntingtin-associated protein / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.342254 KDa
Recombinant expressionOrganism: unidentified baculovirus
SequenceString: MHHHHHHSSG RENLYFQGMA AAAAGLGGGG AGPGPEAGDF LARYRLVSNK LKKRFLRKPN VAEAGEQFGQ LGRELRAQEC LPYAAWCQL AVARCQQALF HGPGEALALT EAARLFLRQE RDARQRLVCP AAYGEPLQAA ASALGAAVRL HLELGQPAAA A ALCLELAA ...String:
MHHHHHHSSG RENLYFQGMA AAAAGLGGGG AGPGPEAGDF LARYRLVSNK LKKRFLRKPN VAEAGEQFGQ LGRELRAQEC LPYAAWCQL AVARCQQALF HGPGEALALT EAARLFLRQE RDARQRLVCP AAYGEPLQAA ASALGAAVRL HLELGQPAAA A ALCLELAA ALRDLGQPAA AAGHFQRAAQ LQLPQLPLAA LQALGEAASC QLLARDYTGA LAVFTRMQRL AREHGSHPVQ SL PPPPPPA PQPGPGATPA LPAALLPPNS GSAAPSPAAL GAFSDVLVRC EVSRVLLLLL LQPPPAKLLP EHAQTLEKYS WEA FDSHGQ ESSGQLPEEL FLLLQSLVMA THEKDTEAIK SLQVEMWPLL TAEQNHLLHL VLQETISPSG QGV

UniProtKB: 40-kDa huntingtin-associated protein

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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

Concentration0.2 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
25.0 mMC8H18N2O4SHEPES
150.0 mMNaClSodium chloride
0.025 %w/vC8H18N2O4SCHAPS
GridModel: Quantifoil R2/4 / Material: GOLD / Mesh: 300 / Support film - Material: GRAPHENE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 51.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 165000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 988456
CTF correctionSoftware - Name: SIMPLE (ver. 3.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 230039
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6x90


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-9pmw:
Structure of HTTQ23-HAP40 complex bound to macrocycles HHL1, HD4 and HL2

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