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- PDB-22ak: GDP human alpha1A/beta3 microtubule -

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Basic information

Entry
Database: PDB / ID: 22ak
TitleGDP human alpha1A/beta3 microtubule
Components
  • Tubulin alpha-1A chain
  • Tubulin beta-3 chain
KeywordsSTRUCTURAL PROTEIN / Cytoskeleton / microtubules / human tubulin isotypes / paclitaxel
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
GUANOSINE-5'-DIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / Tubulin beta-3 chain / Tubulin alpha-1A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.41 Å
AuthorsTi, S.C. / Luo, J.Y. / Khoo, C.J.
Funding support China, Hong Kong, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)224B2707 China
The University Grants Committee, Research Grants Council (RGC)17115924 Hong Kong
The University Grants Committee, Research Grants Council (RGC)C7064-22GF Hong Kong
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
DepositionJan 5, 2026Deposition site: PDBJ / Processing site: PDBJ
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Tubulin beta-3 chain
A: Tubulin alpha-1A chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,6856
Polymers100,6702
Non-polymers1,0154
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 beta-3 chain / Tubulin beta-4 chain / Tubulin beta-III


Mass: 50481.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TUBB3, TUBB4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q13509
#2: Protein Tubulin alpha-1A chain / Alpha-tubulin 3 / Tubulin B-alpha-1 / Tubulin alpha-3 chain


Mass: 50188.441 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TUBA1A, TUBA3 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q71U36, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: GTP, energy-carrying molecule*YM
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: HELICAL ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: GDP human alpha1A/beta3 microtubule / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.16 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 6.8
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: EMS Lacey Carbon
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298.1 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS 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: 1100 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)
EM imaging opticsPhase plate: VOLTA PHASE PLATE

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4.0particle selection
2EPU3.8.1image acquisition
4cryoSPARC4.4.0CTF correction
7Coot0.9.8.7.1model fitting
9PHENIX1.21.2_5419model refinement
12cryoSPARC4.4.0classification
13cryoSPARC4.4.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2811030 / Symmetry type: POINT
Atomic model buildingSpace: REAL
RefinementHighest resolution: 2.41 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00234825
ELECTRON MICROSCOPYf_angle_d0.49847295
ELECTRON MICROSCOPYf_dihedral_angle_d5.7844784
ELECTRON MICROSCOPYf_chiral_restr0.0415190
ELECTRON MICROSCOPYf_plane_restr0.0046155

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