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

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Database: PDB / ID: 5ogc
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 / homologyBeta tubulin, autoregulation binding site / Tubulin/FtsZ, 2-layer sandwich domain / MHC class II antigen presentation / 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 / Tubulin / Kinesin motor domain / Alpha tubulin ...Beta tubulin, autoregulation binding site / Tubulin/FtsZ, 2-layer sandwich domain / MHC class II antigen presentation / 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 / Tubulin / Kinesin motor domain / Alpha tubulin / Beta tubulin / Tubulin/FtsZ, GTPase domain / Tubulin/FtsZ, C-terminal / Separation of Sister Chromatids / Tubulin, conserved site / Kinesin motor domain, conserved site / Recruitment of NuMA to mitotic centrosomes / Tubulin, C-terminal / P-loop containing nucleoside triphosphate hydrolase / Kinesin-like protein / Tubulin/FtsZ, GTPase domain superfamily / Kinesin motor domain superfamily / Tubulin/FtsZ, C-terminal domain superfamily / Tubulin/FtsZ family, GTPase domain / Kinesin motor domain / Tubulin C-terminal domain / Tubulin subunits alpha, beta, and gamma signature. / Tubulin-beta mRNA autoregulation signal. / Kinesin motor domain signature. / Kinesin motor domain profile. / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Recycling pathway of L1 / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / COPI-independent Golgi-to-ER retrograde traffic / Mitotic Prometaphase / The role of GTSE1 in G2/M progression after G2 checkpoint / AURKA Activation by TPX2 / Carboxyterminal post-translational modifications of tubulin / Kinesins / MHC class II antigen presentation / Hedgehog 'off' state / Separation of Sister Chromatids / Resolution of Sister Chromatid Cohesion / RHO GTPases Activate Formins / COPI-dependent Golgi-to-ER retrograde traffic / Mitotic Prometaphase / Kinesins / COPI-dependent Golgi-to-ER retrograde traffic / COPI-mediated anterograde transport / RHO GTPases Activate Formins / Anchoring of the basal body to the plasma membrane / Cilium Assembly / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Intraflagellar transport / RHO GTPases activate IQGAPs / tubulin-dependent ATPase activity / mitotic spindle astral microtubule / kinetochore microtubule / mitotic spindle midzone / male meiotic nuclear division / microtubule plus-end binding / ATP-dependent microtubule motor activity, plus-end-directed / microtubule depolymerization / mitotic metaphase plate congression / regulation of synapse organization / kinesin complex / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / microtubule motor activity / seminiferous tubule development / regulation of microtubule cytoskeleton organization / mitotic sister chromatid segregation / cytoplasmic microtubule / microtubule-based movement / cellular response to interleukin-4 / microtubule-based process / antigen processing and presentation of exogenous peptide antigen via MHC class II / kinetochore / cytoplasmic ribonucleoprotein granule / structural constituent of cytoskeleton / ruffle / microtubule cytoskeleton organization / cellular response to estradiol stimulus / neuron migration / microtubule cytoskeleton / microtubule organizing center / caveola / recycling endosome / neuromuscular junction / protein transport / double-stranded RNA binding / actin binding / mitotic cell cycle / microtubule / microtubule binding / ATPase activity / GTPase activity / GTP binding / ubiquitin protein ligase binding / ATP binding
Function and homology information
Specimen sourceHomo sapiens (human)
Bos taurus (cattle)
Sus scrofa (pig)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / 4.8 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: Jul 12, 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_DOI / _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

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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)144,4379

TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)9170
ΔGint (kcal/M)-70
Surface area (Å2)42980
Number of models2


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) / 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 , 6 types, 6 molecules

#4: Chemical ChemComp-9V5 / 4-chloranyl-2-nitro-1-(phenylsulfonyl)benzene / BIS-TRIS BUFFER

Mass: 297.714 Da / Num. of mol.: 1 / Formula: C12H8ClNO4S
#5: Chemical ChemComp-ZN / ZINC ION

Mass: 65.409 Da / Num. of mol.: 1 / Formula: Zn / Zinc
#6: 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
#8: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE

Mass: 443.201 Da / Num. of mol.: 1 / Formula: C10H15N5O11P2 / Guanosine diphosphate / Comment: GDP (energy-carrying molecule) *YM
#9: 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 with its specific inhibitor BTB-1COMPLEX1,2,30MULTIPLE SOURCES
2Kinesin-8 motor domain neck-linkerCOMPLEX11RECOMBINANT
3Tubulin alpha chainCOMPLEX21NATURAL
4Tubulin beta chainCOMPLEX31NATURAL
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly IDNcbi tax IDOrganism
129606Homo sapiens (human)
239913Bos taurus (cattle)
349823sus 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: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 135382 / Algorithm: FOURIER SPACE / Symmetry type: HELICAL
Atomic model buildingRef protocol: FLEXIBLE FIT / Ref space: REAL
Least-squares processHighest resolution: 4.8 Å

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