PDBsum entry 5ogc

Transport protein

PDB id: 5ogc

Contents

Protein chains

328 a.a.

412 a.a.

426 a.a.

Ligands

9V5

GTP

GDP

TA1

Metals

_ZN

_MG

PDB id:

5ogc

Name:

Transport protein

Title:

Molecular basis of human kinesin-8 function and inhibition

Structure:

Kinesin-like protein kif18a. Chain: k. Synonym: marrow stromal kif18a,ms-kif18a. Engineered: yes. Tubulin alpha chain. Chain: a. Tubulin beta chain. Chain: b. Synonym: beta-tubulin

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kif18a, ok/sw-cl.108. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Bos taurus. Bovine. Organism_taxid: 9913.

Ensemble:

2 models

Authors:

J.Locke,A.P.Joseph,M.Topf,C.A.Moores

Key ref:

J.Locke et al. (2017). Structural basis of human kinesin-8 function and inhibition. Proc Natl Acad Sci U S A, 114, E9539. PubMed id: 29078367

Date:

12-Jul-17 Release date: 25-Oct-17

Protein chain

Q8NI77  (KI18A_HUMAN) -  Kinesin-like protein KIF18A from Homo sapiens

Seq: 898 a.a.

Struc: 328 a.a.

Protein chain

P81947  (TBA1B_BOVIN) -  Tubulin alpha-1B chain from Bos taurus

Seq: 451 a.a.

Struc: 412 a.a.*

Protein chain

P02554  (TBB_PIG) -  Tubulin beta chain from Sus scrofa

Seq: 445 a.a.

Struc: 426 a.a.

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chain A: E.C.3.6.5.- - ?????
• Enzyme class 2: Chains K, B: E.C.?

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Proc Natl Acad Sci U S A 114:E9539 (2017)

PubMed id: 29078367

Structural basis of human kinesin-8 function and inhibition.

J.Locke, A.P.Joseph, A.Peña, M.M.Möckel, T.U.Mayer, M.Topf, C.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 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.