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- PDB-6ta3: Human kinesin-5 motor domain in the GSK-1 state bound to microtub... -

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Basic information

Entry
Database: PDB / ID: 6ta3
TitleHuman kinesin-5 motor domain in the GSK-1 state bound to microtubules (Conformation 1)
Components
  • Kinesin-like protein KIF11
  • Tubulin alpha-1B chain
  • Tubulin beta chain
KeywordsCELL CYCLE / kinesin / microtubule / mitosis / inhibition / motor
Function / homology
Function and homology information


spindle elongation / regulation of mitotic centrosome separation / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Resolution of Sister Chromatid Cohesion / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Mitotic Prometaphase / Carboxyterminal post-translational modifications of tubulin ...spindle elongation / regulation of mitotic centrosome separation / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Resolution of Sister Chromatid Cohesion / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Mitotic Prometaphase / Carboxyterminal post-translational modifications of tubulin / RHOH GTPase cycle / EML4 and NUDC in mitotic spindle formation / Sealing of the nuclear envelope (NE) by ESCRT-III / Kinesins / PKR-mediated signaling / Separation of Sister Chromatids / The role of GTSE1 in G2/M progression after G2 checkpoint / Aggrephagy / plus-end-directed microtubule motor activity / mitotic centrosome separation / Kinesins / RHO GTPases activate IQGAPs / RHO GTPases Activate Formins / kinesin complex / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / MHC class II antigen presentation / Recruitment of NuMA to mitotic centrosomes / microtubule motor activity / COPI-mediated anterograde transport / spindle organization / COPI-dependent Golgi-to-ER retrograde traffic / microtubule-based movement / mitotic spindle assembly / MHC class II antigen presentation / mitotic spindle organization / structural constituent of cytoskeleton / microtubule cytoskeleton organization / spindle / neuron migration / spindle pole / mitotic spindle / mitotic cell cycle / microtubule cytoskeleton / microtubule binding / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / microtubule / ciliary basal body / cell division / GTPase activity / intracellular membrane-bounded organelle / protein kinase binding / GTP binding / protein-containing complex / ATP binding / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Kinesin-associated microtubule-binding domain / Kinesin-associated microtubule-binding / : / : / Kinesin motor domain / Kinesin / Helix hairpin bin / Tubulin/FtsZ, C-terminal domain / Tubulin/FtsZ, GTPase domain / Kinesin motor domain signature. ...Kinesin-associated microtubule-binding domain / Kinesin-associated microtubule-binding / : / : / Kinesin motor domain / Kinesin / Helix hairpin bin / Tubulin/FtsZ, C-terminal domain / Tubulin/FtsZ, GTPase domain / Kinesin motor domain signature. / Kinesin motor domain, conserved site / Kinesin motor domain / Kinesin motor domain profile. / Kinesin motor, catalytic domain. ATPase. / Kinesin motor domain / 60s Ribosomal Protein L30; Chain: A; / Kinesin motor domain superfamily / Tubulin-beta mRNA autoregulation signal. / Alpha tubulin / 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 / Helix Hairpins / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / Chem-MZK / Tubulin beta chain / Kinesin-like protein KIF11 / Tubulin alpha-1B chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Sus scrofa (pig)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsPena, A. / Sweeney, A. / Cook, A.D. / Moores, C.A. / Topf, M.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Wellcome Trust202679/Z/16/Z and 206166/Z/17/Z United Kingdom
Medical Research Council (United Kingdom)MR/J003867/1 United Kingdom
Medical Research Council (United Kingdom)MR/N013867/1 United Kingdom
Citation
Journal: Structure / Year: 2020
Title: Structure of Microtubule-Trapped Human Kinesin-5 and Its Mechanism of Inhibition Revealed Using Cryoelectron Microscopy.
Authors: Alejandro Peña / Aaron Sweeney / Alexander D Cook / Julia Locke / Maya Topf / Carolyn A Moores /
Abstract: Kinesin-5 motors are vital mitotic spindle components, and disruption of their function perturbs cell division. We investigated the molecular mechanism of the human kinesin-5 inhibitor GSK-1, which ...Kinesin-5 motors are vital mitotic spindle components, and disruption of their function perturbs cell division. We investigated the molecular mechanism of the human kinesin-5 inhibitor GSK-1, which allosterically promotes tight microtubule binding. GSK-1 inhibits monomeric human kinesin-5 ATPase and microtubule gliding activities, and promotes the motor's microtubule stabilization activity. Using cryoelectron microscopy, we determined the 3D structure of the microtubule-bound motor-GSK-1 at 3.8 Å overall resolution. The structure reveals that GSK-1 stabilizes the microtubule binding surface of the motor in an ATP-like conformation, while destabilizing regions of the motor around the empty nucleotide binding pocket. Density corresponding to GSK-1 is located between helix-α4 and helix-α6 in the motor domain at its interface with the microtubule. Using a combination of difference mapping and protein-ligand docking, we characterized the kinesin-5-GSK-1 interaction and further validated this binding site using mutagenesis. This work opens up new avenues of investigation of kinesin inhibition and spindle perturbation.
#1: Journal: To Be Published
Title: Mechanism of microtubule-trapped human kinesin-5 inhibition revealed using cryo-EM
Authors: Pena, A.P. / Sweeney, A.
History
DepositionOct 29, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2020Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id
Revision 1.1Apr 9, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: database_2 / em_admin / Data content type: EM metadata / EM metadata / EM metadata
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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Assembly

Deposited unit
B: Tubulin beta chain
A: Tubulin alpha-1B chain
K: Kinesin-like protein KIF11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,0038
Polymers140,6213
Non-polymers1,3825
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area6720 Å2
ΔGint-51 kcal/mol
Surface area44220 Å2
MethodPISA

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Components

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Protein , 3 types, 3 molecules BAK

#1: Protein Tubulin beta chain / Beta-tubulin


Mass: 48113.129 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: P02554
#2: Protein Tubulin alpha-1B chain / Alpha-tubulin ubiquitous / Tubulin K-alpha-1 / Tubulin alpha-ubiquitous chain


Mass: 48780.117 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: Q2XVP4
#3: Protein Kinesin-like protein KIF11 / Kinesin-like protein 1 / Kinesin-like spindle protein HKSP / Kinesin-related motor protein Eg5 / ...Kinesin-like protein 1 / Kinesin-like spindle protein HKSP / Kinesin-related motor protein Eg5 / Thyroid receptor-interacting protein 5 / TRIP-5


Mass: 43727.461 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIF11, EG5, KNSL1, TRIP5 / Production host: Escherichia coli (E. coli) / References: UniProt: P52732

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Non-polymers , 3 types, 5 molecules

#4: Chemical ChemComp-G2P / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-CPP, energy-carrying molecule analogue*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-MZK / 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1~{H}-quinolin-2-one


Mass: 291.268 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12F3NO / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Ternary complex of Human Kinesin 5 and microtubulesCOMPLEX#1-#30MULTIPLE SOURCES
2Tubulin alpha-1B chain and Tubulin beta chainCOMPLEX#1-#21NATURAL
3Kinesin-like protein KIF11COMPLEX#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Sus scrofa (pig)9823
23Homo sapiens (human)9606
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -25.7 ° / Axial rise/subunit: 8.9 Å / Axial symmetry: C1
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 507219 / Symmetry type: HELICAL

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