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- PDB-5oam: Molecular basis of human kinesin-8 function and inhibition -

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Database: PDB / ID: 5oam
TitleMolecular basis of human kinesin-8 function and inhibition
  • Kinesin-like protein KIF18A
  • Tubulin alpha chain
  • Tubulin beta chain
KeywordsTRANSPORT PROTEIN / Cytoskeleton / Motor protein / Kinesin
Function / homologyTubulin, C-terminal / Kinesin motor domain superfamily / Tubulin / Kinesin motor domain / Alpha tubulin / Beta tubulin / Tubulin/FtsZ, GTPase domain / Tubulin/FtsZ, C-terminal / Beta tubulin, autoregulation binding site / Tubulin, conserved site ...Tubulin, C-terminal / Kinesin motor domain superfamily / Tubulin / Kinesin motor domain / Alpha tubulin / Beta tubulin / Tubulin/FtsZ, GTPase domain / Tubulin/FtsZ, C-terminal / Beta tubulin, autoregulation binding site / Tubulin, conserved site / Tubulin/FtsZ, 2-layer sandwich domain / Kinesin motor domain, conserved site / Hedgehog 'off' state / P-loop containing nucleoside triphosphate hydrolase / Kinesin-like protein / Tubulin/FtsZ, GTPase domain superfamily / Tubulin/FtsZ, C-terminal domain superfamily / Recycling pathway of L1 / MHC class II antigen presentation / Recruitment of mitotic centrosome proteins and complexes / Loss of Nlp from mitotic centrosomes / HSP90 chaperone cycle for steroid hormone receptors (SHR) / Regulation of PLK1 Activity at G2/M Transition / Resolution of Sister Chromatid Cohesion / Separation of Sister Chromatids / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Tubulin/FtsZ family, GTPase domain / Kinesin motor domain profile. / Kinesin motor domain signature. / Tubulin-beta mRNA autoregulation signal. / Tubulin subunits alpha, beta, and gamma signature. / Tubulin C-terminal domain / Kinesin motor domain / Cilium Assembly / Recruitment of NuMA to mitotic centrosomes / COPI-dependent Golgi-to-ER retrograde traffic / Mitotic Prometaphase / RHO GTPases Activate Formins / Resolution of Sister Chromatid Cohesion / Separation of Sister Chromatids / MHC class II antigen presentation / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Kinesins / Carboxyterminal post-translational modifications of tubulin / AURKA Activation by TPX2 / The role of GTSE1 in G2/M progression after G2 checkpoint / Mitotic Prometaphase / COPI-independent Golgi-to-ER retrograde traffic / COPI-dependent Golgi-to-ER retrograde traffic / Anchoring of the basal body to the plasma membrane / Intraflagellar transport / RHO GTPases activate IQGAPs / Kinesins / COPI-mediated anterograde transport / RHO GTPases Activate Formins / Hedgehog 'on' state / tubulin-dependent ATPase activity / kinetochore microtubule / mitotic spindle midzone / male meiotic nuclear division / microtubule plus-end binding / seminiferous tubule development / microtubule depolymerization / ATP-dependent microtubule motor activity, plus-end-directed / mitotic metaphase plate congression / kinesin complex / retrograde vesicle-mediated transport, Golgi to ER / regulation of microtubule cytoskeleton organization / cytoplasmic microtubule / cellular response to interleukin-4 / recycling endosome / microtubule-based process / microtubule cytoskeleton organization / antigen processing and presentation of exogenous peptide antigen via MHC class II / kinetochore / microtubule-based movement / cytoplasmic ribonucleoprotein granule / structural constituent of cytoskeleton / ruffle / cellular response to estradiol stimulus / microtubule cytoskeleton / microtubule organizing center / caveola / double-stranded RNA binding / protein transport / actin binding / microtubule / microtubule binding / GTPase activity / myelin sheath / GTP binding / ubiquitin protein ligase binding / ATP binding / nucleus / cytosol / cytoplasm / Tubulin alpha chain / Tubulin beta chain / Tubulin alpha-1B chain / Kinesin-like protein KIF18A
Function and homology information
Specimen sourceHomo sapiens (human)
Bos taurus (cattle)
Sus scrofa (pig)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / 5.5 Å resolution
AuthorsLocke, J. / Joseph, A.P. / Topf, M. / Moores, C.A.
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2017
Title: Structural basis of human kinesin-8 function and inhibition.
Authors: Julia Locke / Agnel Praveen Joseph / Alejandro Peña / Martin M Möckel / Thomas U Mayer / Maya Topf / Carolyn A Moores
Abstract: Kinesin motors play diverse roles in mitosis and are targets for antimitotic drugs. The clinical significance of these motors emphasizes the importance of understanding the molecular basis of their ...Kinesin motors play diverse roles in mitosis and are targets for antimitotic drugs. The clinical significance of these motors emphasizes the importance of understanding the molecular basis of their function. Equally important, investigations into the modes of inhibition of these motors provide crucial information about their molecular mechanisms. Kif18A regulates spindle microtubules through its dual functionality, with microtubule-based stepping and regulation of microtubule dynamics. We investigated the mechanism of Kif18A and its inhibition by the small molecule BTB-1. The Kif18A motor domain drives ATP-dependent plus-end microtubule gliding, and undergoes conformational changes consistent with canonical mechanisms of plus-end-directed motility. The Kif18A motor domain also depolymerizes microtubule plus and minus ends. BTB-1 inhibits both of these microtubule-based Kif18A activities. A reconstruction of BTB-1-bound, microtubule-bound Kif18A, in combination with computational modeling, identified an allosteric BTB-1-binding site near loop5, where it blocks the ATP-dependent conformational changes that we characterized. Strikingly, BTB-1 binding is close to that of well-characterized Kif11 inhibitors that block tight microtubule binding, whereas BTB-1 traps Kif18A on the microtubule. Our work highlights a general mechanism of kinesin inhibition in which small-molecule binding near loop5 prevents a range of conformational changes, blocking motor function.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Jun 23, 2017 / Release: Oct 25, 2017
RevisionDateData content typeGroupCategoryItemProviderType
1.0Oct 25, 2017Structure modelrepositoryInitial release
1.1Nov 8, 2017Structure modelDatabase referencescitation / citation_author_citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
1.2Nov 15, 2017Structure modelDatabase referencescitation_citation.journal_volume / _citation.page_first / _citation.page_last

Structure visualization

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Deposited unit
K: Kinesin-like protein KIF18A
A: Tubulin alpha chain
B: Tubulin beta chain
hetero molecules

Theoretical massNumber of molelcules
Total (without water)144,1398

  • idetical with deposited unit
  • defined by author
  • Evidence: microscopy, Complex assembly was verified by negative stain microscopy
  • Download structure data
TypeNameSymmetry operationNumber
identity operation1_5551


Protein/peptide , 3 types, 3 molecules KAB

#1: Protein/peptide Kinesin-like protein KIF18A / Marrow stromal KIF18A / MS-KIF18A

Mass: 42213.938 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: KIF18A, OK/SW-cl.108 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): CodonPlus-RIL / References: UniProt: Q8NI77
#2: Protein/peptide Tubulin alpha chain

Mass: 50107.238 Da / Num. of mol.: 1 / Source: (natural) Bos taurus (cattle) / References: UniProt: F2Z4C1, UniProt: P81947*PLUS
#3: Protein/peptide Tubulin beta chain / Beta-tubulin

Mass: 49907.770 Da / Num. of mol.: 1 / Source: (natural) Sus scrofa (pig) / References: UniProt: P02554

Non-polymers , 5 types, 5 molecules

#4: Chemical ChemComp-ZN / ZINC ION

Mass: 65.409 Da / Num. of mol.: 1 / Formula: Zn / Zinc
#5: Chemical ChemComp-MG / MAGNESIUM ION

Mass: 24.305 Da / Num. of mol.: 1 / Formula: Mg / Magnesium

Mass: 523.180 Da / Num. of mol.: 1 / Formula: C10H16N5O14P3 / Guanosine triphosphate / Comment: GTP (energy-carrying molecule) *YM
#7: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE

Mass: 443.201 Da / Num. of mol.: 1 / Formula: C10H15N5O11P2 / Guanosine diphosphate / Comment: GDP (energy-carrying molecule) *YM
#8: Chemical ChemComp-TA1 / TAXOL

Mass: 853.906 Da / Num. of mol.: 1 / Formula: C47H51NO14 / Paclitaxel

Experimental details


EM experimentAggregation state: FILAMENT / Reconstruction method: helical reconstruction

Sample preparation

IDNameTypeEntity IDParent IDSource
113-Protofilament microtuble-bound human Kinesin-8 motor domain neck-linker without nucleotideCOMPLEX1, 2, 30MULTIPLE SOURCES
2Tubulin, alphaCOMPLEX21NATURAL
4Kinesin-8 motor domain neck-linkerCOMPLEX11RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly IDNcbi tax IDOrganism
149606Homo sapiens (human)
229913Bos taurus (cattle)
339823Sus scrofa (pig)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: C-flat-2/2
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 kelvins

Electron microscopy imaging

Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company
MicroscopyMicroscope model: FEI POLARA 300 / Details: FEI Polara
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus min: 500 nm / Calibrated defocus max: 3500 nm / Cs: 2.3 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: OTHER
Image recordingAverage exposure time: 2 sec. / Electron dose: 5 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum
Image scansWidth: 3840 / Height: 3712 / Movie frames/image: 5


EM software
2SerialEMimage acquisition
4CTFFIND3CTF correction
7Chimeramodel fitting
9SPIDERinitial Euler assignment
10SPIDERfinal Euler assignment
12FREALIGN3D reconstruction
13Flex-EMmodel refinement
14Flex-EMmodel fitting
Helical symmertyAngular rotation/subunit: 0 deg. / Axial rise/subunit: 81 Å / Axial symmetry: C1
3D reconstructionResolution: 5.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 70395 / Algorithm: FOURIER SPACE / Symmetry type: HELICAL
Atomic model buildingRef protocol: FLEXIBLE FIT / Ref space: REAL

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