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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 / dorsal root ganglion development / Post-chaperonin tubulin folding pathway / axonemal microtubule / Cilium Assembly / cytoskeleton-dependent intracellular transport / organelle transport along microtubule / Carboxyterminal post-translational modifications of tubulin / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / forebrain morphogenesis ...netrin receptor binding / dorsal root ganglion development / Post-chaperonin tubulin folding pathway / axonemal microtubule / Cilium Assembly / cytoskeleton-dependent intracellular transport / organelle transport along microtubule / Carboxyterminal post-translational modifications of tubulin / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / forebrain morphogenesis / Sealing of the nuclear envelope (NE) by ESCRT-III / Intraflagellar transport / cerebellar cortex morphogenesis / glial cell differentiation / neuron projection arborization / dentate gyrus development / Formation of tubulin folding intermediates by CCT/TriC / flagellated sperm motility / Gap junction assembly / Kinesins / Prefoldin mediated transfer of substrate to CCT/TriC / pyramidal neuron differentiation / Assembly and cell surface presentation of NMDA receptors / COPI-independent Golgi-to-ER retrograde traffic / response to L-glutamate / centrosome cycle / COPI-dependent Golgi-to-ER retrograde traffic / smoothened signaling pathway / regulation of synapse organization / startle response / motor behavior / Recycling pathway of L1 / microtubule polymerization / locomotory exploration behavior / response to tumor necrosis factor / response to mechanical stimulus / sperm flagellum / microtubule-based process / RHO GTPases activate IQGAPs / intercellular bridge / 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 / MHC class II antigen presentation / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / homeostasis of number of cells within a tissue / Mitotic Prometaphase / cellular response to calcium ion / EML4 and NUDC in mitotic spindle formation / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / AURKA Activation by TPX2 / axon guidance / Resolution of Sister Chromatid Cohesion / cell periphery / adult locomotory behavior / Translocation of SLC2A4 (GLUT4) to the plasma membrane / filopodium / neuromuscular junction / RHO GTPases Activate Formins / intracellular protein transport / cerebral cortex development / PKR-mediated signaling / synapse organization / visual learning / recycling endosome / structural constituent of cytoskeleton / microtubule cytoskeleton organization / neuron migration / memory / HCMV Early Events / Aggrephagy / cytoplasmic ribonucleoprotein granule / The role of GTSE1 in G2/M progression after G2 checkpoint / mitotic spindle / Separation of Sister Chromatids / Regulation of PLK1 Activity at G2/M Transition / mitotic cell cycle / lamellipodium / growth cone / microtubule cytoskeleton / neuron apoptotic process / gene expression / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / microtubule / cilium / protein heterodimerization activity / cell division / axon / hydrolase activity / neuronal cell body / GTPase activity / dendrite / GTP binding / protein-containing complex binding
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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