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- EMDB-65886: GMPCPP-stabilized human alpha1A/beta3 S239C microtubule -

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Entry
Database: EMDB / ID: EMD-65886
TitleGMPCPP-stabilized human alpha1A/beta3 S239C microtubule
Map dataSharpened symmetry-expanded map of the GMPCPP-stabilized alpha1A/beta3 S239C microtubule
Sample
  • Complex: GMPCPP-stabilized alpha1A/beta3 s239c microtubule
    • Protein or peptide: Tubulin alpha-1A chain
    • Protein or peptide: Tubulin beta-3 chain
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER
KeywordsCytoskeleton / microtubules / human tubulin isotypes / paclitaxel / STRUCTURAL PROTEIN
Function / homology
Function and homology information


netrin receptor binding / pyramidal neuron differentiation / glial cell differentiation / dorsal root ganglion development / Post-chaperonin tubulin folding pathway / dentate gyrus development / cytoskeleton-dependent intracellular transport / Cargo trafficking to the periciliary membrane / Carboxyterminal post-translational modifications of tubulin / axonemal microtubule ...netrin receptor binding / pyramidal neuron differentiation / glial cell differentiation / dorsal root ganglion development / Post-chaperonin tubulin folding pathway / dentate gyrus development / cytoskeleton-dependent intracellular transport / Cargo trafficking to the periciliary membrane / Carboxyterminal post-translational modifications of tubulin / axonemal microtubule / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / organelle transport along microtubule / forebrain morphogenesis / cerebellar cortex morphogenesis / Sealing of the nuclear envelope (NE) by ESCRT-III / Intraflagellar transport / Formation of tubulin folding intermediates by CCT/TriC / neuron projection arborization / Gap junction assembly / smoothened signaling pathway / homeostasis of number of cells within a tissue / motor behavior / Kinesins / Prefoldin mediated transfer of substrate to CCT/TriC / response to L-glutamate / Assembly and cell surface presentation of NMDA receptors / COPI-independent Golgi-to-ER retrograde traffic / centrosome cycle / sperm principal piece / COPI-dependent Golgi-to-ER retrograde traffic / startle response / 'de novo' protein folding / intercellular bridge / flagellated sperm motility / regulation of synapse organization / locomotory exploration behavior / sperm end piece / Recycling pathway of L1 / microtubule polymerization / ciliary tip / response to tumor necrosis factor / response to mechanical stimulus / neuron apoptotic process / adult locomotory behavior / sperm flagellum / RHO GTPases activate IQGAPs / microtubule-based process / Hedgehog 'off' state / COPI-mediated anterograde transport / Activation of AMPK downstream of NMDARs / condensed chromosome / peptide binding / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / cellular response to calcium ion / MHC class II antigen presentation / visual learning / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Mitotic Prometaphase / axon guidance / EML4 and NUDC in mitotic spindle formation / AURKA Activation by TPX2 / Resolution of Sister Chromatid Cohesion / cell periphery / Translocation of SLC2A4 (GLUT4) to the plasma membrane / filopodium / neuromuscular junction / neuron migration / memory / cerebral cortex development / RHO GTPases Activate Formins / intracellular protein transport / synapse organization / microtubule cytoskeleton organization / PKR-mediated signaling / recycling endosome / mitotic spindle / structural constituent of cytoskeleton / cytoplasmic ribonucleoprotein granule / HCMV Early Events / microtubule cytoskeleton / Aggrephagy / cilium / The role of GTSE1 in G2/M progression after G2 checkpoint / Separation of Sister Chromatids / Regulation of PLK1 Activity at G2/M Transition / neuron differentiation / mitotic cell cycle / lamellipodium / growth cone / protein-folding chaperone binding / microtubule binding / microtubule / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / protein stabilization / protein heterodimerization activity / axon
Similarity search - Function
Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / Beta tubulin, autoregulation binding site / Beta tubulin / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain / Tubulin, conserved site / Tubulin subunits alpha, beta, and gamma signature. / Tubulin/FtsZ family, C-terminal domain ...Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / Beta tubulin, autoregulation binding site / Beta tubulin / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain / Tubulin, conserved site / Tubulin subunits alpha, beta, and gamma signature. / 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 beta-3 chain / Tubulin alpha-1A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.26 Å
AuthorsTi SC / Luo JY / Khoo CJ
Funding support Hong Kong, China, 3 items
OrganizationGrant numberCountry
The University Grants Committee, Research Grants Council (RGC)17115924 Hong Kong
The University Grants Committee, Research Grants Council (RGC)C7064-22GF Hong Kong
National Natural Science Foundation of China (NSFC)224B2707 China
CitationJournal: Nat Chem Biol / Year: 2026
Title: An evolution-conserved allosteric network in human tubulin governs paclitaxel efficacy.
Authors: Jingyi Luo / Chen Jing Khoo / Weixin Chen / Zheng Liu / Boxuan Li / Wei Sin Lau / Xiang David Li / Shih-Chieh Ti /
Abstract: Tubulin-targeting agents such as paclitaxel have been a cornerstone of cancer treatment. However, the molecular basis by which prognosis-associated tubulin isotypes and mutations (that is, variants) ...Tubulin-targeting agents such as paclitaxel have been a cornerstone of cancer treatment. However, the molecular basis by which prognosis-associated tubulin isotypes and mutations (that is, variants) affect drug efficacy remains unclear. Here we reveal that evolutionarily conserved tubulin residues modulate the allosteric network to determine paclitaxel efficacy. The paclitaxel resistance of human β3-tubulin depends on a residue distant from the taxane-binding pocket. The ~2.3 Å-resolution cryo-EM microtubule reconstructions demonstrate that the paclitaxel-sensitizing tubulin mutation induces allostery at the paclitaxel-binding site, intertubulin interactions and nucleotide-binding pockets. In particular, the reoriented guanine triphosphate (GTP)-hydrolyzing catalytic α-tubulin E254 residue enhances the GTP cap, reducing the catastrophe frequency of dynamic microtubules. Examining genome-edited cancer cells with the paclitaxel-sensitized mutant β3-tubulin indicates that the affinities of tubulin variants for paclitaxel determine drug efficacy. Our findings provide mechanistic insights into the development of new tubulin-targeting therapeutics not only for cancer but also for tubulinopathies associated with mutations in specific tubulin isotypes.
History
DepositionAug 18, 2025-
Header (metadata) releaseApr 1, 2026-
Map releaseApr 1, 2026-
UpdateApr 29, 2026-
Current statusApr 29, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_65886.png

Downloads & links

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Map

FileDownload / File: emd_65886.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened symmetry-expanded map of the GMPCPP-stabilized alpha1A/beta3 S239C microtubule
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 512 pix.
= 489.318 Å		0.96 Å/pix.
x 512 pix.
= 489.318 Å		0.96 Å/pix.
x 512 pix.
= 489.318 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9557 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.147
Minimum - Maximum-0.95739526 - 2.3989975
Average (Standard dev.)0.0011685449 (±0.042549036)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 489.3184 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_65886_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: C1-symmetry map of the GMPCPP-stabilized alpha1A/beta3 S239C microtubule...

Fileemd_65886_additional_1.map
AnnotationC1-symmetry map of the GMPCPP-stabilized alpha1A/beta3 S239C microtubule
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map of symmetry expanded map of GMPCPP-stabilized alpha1A/beta3...

Fileemd_65886_half_map_1.map
AnnotationHalf-map of symmetry expanded map of GMPCPP-stabilized alpha1A/beta3 S239C microtubule
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map of symmetry expanded map of GMPCPP-stabilized alpha1A/beta3...

Fileemd_65886_half_map_2.map
AnnotationHalf-map of symmetry expanded map of GMPCPP-stabilized alpha1A/beta3 S239C microtubule
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : GMPCPP-stabilized alpha1A/beta3 s239c microtubule

EntireName: GMPCPP-stabilized alpha1A/beta3 s239c microtubule
Components
  • Complex: GMPCPP-stabilized alpha1A/beta3 s239c microtubule
    • Protein or peptide: Tubulin alpha-1A chain
    • Protein or peptide: Tubulin beta-3 chain
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER

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Supramolecule #1: GMPCPP-stabilized alpha1A/beta3 s239c microtubule

SupramoleculeName: GMPCPP-stabilized alpha1A/beta3 s239c microtubule / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 0.16 kDa/nm

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Macromolecule #1: Tubulin alpha-1A chain

MacromoleculeName: Tubulin alpha-1A chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.188441 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MRECISIHVG QAGVQIGNAC WELYCLEHGI QPDGQMPSDK TIGGGDDSFN TFFSETGAGK HVPRAVFVDL EPTVIDEVRT GTYRQLFHP EQLITGKEDA ANNYARGHYT IGKEIIDLVL DRIRKLADQC TGLQGFLVFH SFGGGTGSGF TSLLMERLSV D YGKKSKLE ...String:
MRECISIHVG QAGVQIGNAC WELYCLEHGI QPDGQMPSDK TIGGGDDSFN TFFSETGAGK HVPRAVFVDL EPTVIDEVRT GTYRQLFHP EQLITGKEDA ANNYARGHYT IGKEIIDLVL DRIRKLADQC TGLQGFLVFH SFGGGTGSGF TSLLMERLSV D YGKKSKLE FSIYPAPQVS TAVVEPYNSI LTTHTTLEHS DCAFMVDNEA IYDICRRNLD IERPTYTNLN RLIGQIVSSI TA SLRFDGA LNVDLTEFQT NLVPYPRIHF PLATYAPVIS AEKAYHEQLS VAEITNACFE PANQMVKCDP RHGKYMACCL LYR GDVVPK DVNAAIATIK TKRTIQFVDW CPTGFKVGIN YQPPTVVPGG DLAKVQRAVC MLSNTTAIAE AWARLDHKFD LMYA KRAFV HWYVGEGMEE GEFSEAREDM AALEKDYEEV GVDSVEGEGE EEGEEY

UniProtKB: Tubulin alpha-1A chain

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Macromolecule #2: Tubulin beta-3 chain

MacromoleculeName: Tubulin beta-3 chain / type: protein_or_peptide / ID: 2 / Details: human beta3 tubulin mutant S239C / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.497586 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MREIVHIQAG QCGNQIGAKF WEVISDEHGI DPSGNYVGDS DLQLERISVY YNEASSHKYV PRAILVDLEP GTMDSVRSGA FGHLFRPDN FIFGQSGAGN NWAKGHYTEG AELVDSVLDV VRKECENCDC LQGFQLTHSL GGGTGSGMGT LLISKVREEY P DRIMNTFS ...String:
MREIVHIQAG QCGNQIGAKF WEVISDEHGI DPSGNYVGDS DLQLERISVY YNEASSHKYV PRAILVDLEP GTMDSVRSGA FGHLFRPDN FIFGQSGAGN NWAKGHYTEG AELVDSVLDV VRKECENCDC LQGFQLTHSL GGGTGSGMGT LLISKVREEY P DRIMNTFS VVPSPKVSDT VVEPYNATLS IHQLVENTDE TYCIDNEALY DICFRTLKLA TPTYGDLNHL VSATMSGVTT CL RFPGQLN ADLRKLAVNM VPFPRLHFFM PGFAPLTARG SQQYRALTVP ELTQQMFDAK NMMAACDPRH GRYLTVATVF RGR MSMKEV DEQMLAIQSK NSSYFVEWIP NNVKVAVCDI PPRGLKMSST FIGNSTAIQE LFKRISEQFT AMFRRKAFLH WYTG EGMDE MEFTEAESNM NDLVSEYQQY QDATAEEEGE MYEDDEEESE AQGPK

UniProtKB: Tubulin beta-3 chain

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Macromolecule #3: GUANOSINE-5'-TRIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 1 / Formula: GTP
Molecular weightTheoretical: 523.18 Da
Chemical component information

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER

MacromoleculeName: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / type: ligand / ID: 5 / Number of copies: 1 / Formula: G2P
Molecular weightTheoretical: 521.208 Da
Chemical component information

ChemComp-G2P:
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GMP-CPP, energy-carrying molecule analogue*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statehelical array

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 6.8
GridModel: EMS Lacey Carbon / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298.1 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsPhase plate: VOLTA PHASE PLATE
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.1 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 603806
CTF correctionSoftware - Name: cryoSPARC (ver. 4.4.0) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: ModelAngelo
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.26 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.0) / Number images used: 527919
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.4.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-9wd9:
GMPCPP-stabilized human alpha1A/beta3 S239C microtubule

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