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- PDB-8x9p: HURP (428-534)-alpha-tubulin-beta-tubulin complex -

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Basic information

Entry
Database: PDB / ID: 8x9p
TitleHURP (428-534)-alpha-tubulin-beta-tubulin complex
Components
  • Disks large-associated protein 5,Green fluorescent protein
  • Tubulin alpha chain
  • Tubulin beta chain
KeywordsCELL CYCLE / HURP / tubulin / drug resistance / mitosis
Function / homology
Function and homology information


mitotic chromosome movement towards spindle pole / signaling / kinetochore assembly / positive regulation of mitotic metaphase/anaphase transition / spindle pole centrosome / NOTCH3 Intracellular Domain Regulates Transcription / centrosome localization / microtubule-based process / regulation of mitotic cell cycle / bioluminescence ...mitotic chromosome movement towards spindle pole / signaling / kinetochore assembly / positive regulation of mitotic metaphase/anaphase transition / spindle pole centrosome / NOTCH3 Intracellular Domain Regulates Transcription / centrosome localization / microtubule-based process / regulation of mitotic cell cycle / bioluminescence / mitotic spindle organization / generation of precursor metabolites and energy / chromosome segregation / structural constituent of cytoskeleton / microtubule cytoskeleton organization / neuron migration / mitotic spindle / mitotic cell cycle / microtubule binding / microtubule / hydrolase activity / GTPase activity / GTP binding / metal ion binding / nucleus / cytoplasm / cytosol
Similarity search - Function
SAPAP family / Guanylate-kinase-associated protein (GKAP) protein / Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / Beta tubulin, autoregulation binding site / Beta tubulin / Green fluorescent protein, GFP / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain ...SAPAP family / Guanylate-kinase-associated protein (GKAP) protein / Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / Beta tubulin, autoregulation binding site / Beta tubulin / Green fluorescent protein, GFP / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain / Tubulin, conserved site / Tubulin subunits alpha, beta, and gamma signature. / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Tubulin/FtsZ family, C-terminal domain / Tubulin/FtsZ-like, C-terminal domain / Tubulin/FtsZ, C-terminal / Tubulin/FtsZ, 2-layer sandwich domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ, GTPase domain / Tubulin/FtsZ, GTPase domain superfamily
Similarity search - Domain/homology
Tubulin alpha chain / Tubulin beta chain / Green fluorescent protein / Disks large-associated protein 5
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.54 Å
AuthorsChen, P.-P. / Hsia, K.-C.
Funding support Taiwan, 1items
OrganizationGrant numberCountry
Academia Sinica (Taiwan)AS-IVA-112-L05 Taiwan
CitationJournal: Nat Commun / Year: 2024
Title: HURP binding to the vinca domain of β-tubulin accounts for cancer drug resistance.
Authors: Athira Saju / Po-Pang Chen / Tzu-Han Weng / Su-Yi Tsai / Akihiro Tanaka / Yu-Ting Tseng / Chih-Chia Chang / Chun-Hsiung Wang / Yuta Shimamoto / Kuo-Chiang Hsia /
Abstract: Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule- ...Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule-associated protein displaying heightened expression across various cancer types, reduces cancer cells' sensitivity to vinca-alkaloid drugs upon overexpression. However, the molecular basis behind this drug resistance remains unknown. Here we discover a tubulin-binding domain within HURP, and establish its role in regulating microtubule growth. Cryo-EM analysis reveals interactions between HURP's tubulin-binding domain and the vinca domain on β-tubulin -- the site targeted by vinca alkaloid drugs. Importantly, HURP competes directly with vinorelbine, a vinca alkaloid-based chemotherapeutic agent, countering microtubule growth defects caused by vinorelbine both in vitro and in vivo. Our findings elucidate a mechanism driving drug resistance in HURP-overexpressing cancer cells and emphasize HURP tubulin-binding domain's role in mitotic spindle assembly. This underscores its potential as a therapeutic target to improve cancer treatment.
History
DepositionNov 30, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 23, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tubulin alpha chain
B: Tubulin beta chain
C: Disks large-associated protein 5,Green fluorescent protein


Theoretical massNumber of molelcules
Total (without water)172,8813
Polymers172,8813
Non-polymers00
Water00
1


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

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Components

#1: Protein Tubulin alpha chain


Mass: 48769.988 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Production host: Bos taurus (domestic cattle) / References: UniProt: A0A0M3KKT1
#2: Protein Tubulin beta chain


Mass: 47940.945 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Production host: Bos taurus (domestic cattle) / References: UniProt: P02554
#3: Protein Disks large-associated protein 5,Green fluorescent protein / DAP-5 / Discs large homolog 7 / Disks large-associated protein DLG7 / Hepatoma up-regulated protein / HURP


Mass: 76169.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DLGAP5, DLG7, KIAA0008, GFP / Production host: Bacteria (eubacteria) / References: UniProt: Q15398, UniProt: P42212
Has protein modificationN

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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: HURP (428-534)-alpha-tubulin-beta-tubulin complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Bacteria (eubacteria)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER
VitrificationCryogen name: ETHANE

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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 FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 248567 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0047839
ELECTRON MICROSCOPYf_angle_d0.65410619
ELECTRON MICROSCOPYf_dihedral_angle_d4.0051055
ELECTRON MICROSCOPYf_chiral_restr0.0441158
ELECTRON MICROSCOPYf_plane_restr0.0041396

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