5O7A | pdb_00005o7a

Quinolin-6-yloxyacetamides are microtubule destabilizing agents that bind to the colchicine site of tubulin

PDB DOI: https://doi.org/10.2210/pdb5O7A/pdb

Classification: MOTOR PROTEIN
Organism(s): Bos taurus, Rattus norvegicus, Gallus gallus
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2017-06-08 Released: 2017-07-05
Deposition Author(s): Sharma, A., Olieric, N., Steinmetz, M.O.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.50 Å
R-Value Free:
0.256 (Depositor), 0.260 (DCC)
R-Value Work:
0.204 (Depositor), 0.200 (DCC)
R-Value Observed:
0.205 (Depositor)

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin.

Sharma, A., Saez-Calvo, G., Olieric, N., de Asis Balaguer, F., Barasoain, I., Lamberth, C., Diaz, J.F., Steinmetz, M.O.

(2017) Int J Mol Sci 18

PubMed: 28640209 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.3390/ijms18071336
Primary Citation of Related Structures:
5O7A

PubMed Abstract:
Quinolin-6-yloxyacetamides (QAs) are a chemical class of tubulin polymerization inhibitors that were initially identified as fungicides. Here, we report that QAs are potent anti-proliferative agents against human cancer cells including ones that are drug-resistant. QAs act by disrupting the microtubule cytoskeleton and by causing severe mitotic defects. We further demonstrate that QAs inhibit tubulin polymerization in vitro. The high resolution crystal structure of the tubulin-QA complex revealed that QAs bind to the colchicine site on tubulin, which is targeted by microtubule-destabilizing agents such as colchicine and nocodazole. Together, our data establish QAs as colchicine-site ligands and explain the molecular mechanism of microtubule destabilization by this class of compounds. They further extend our structural knowledge on antitubulin agents and thus should aid in the development of new strategies for the rational design of ligands against multidrug-resistant cancer cells.

Organizational Affiliation

Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen, Switzerland. ashwani.sharma@psi.ch.

Macromolecule Content

Total Structure Weight: 264.88 kDa
Atom Count: 16,982
Modelled Residue Count: 2,089
Deposited Residue Count: 2,319
Unique protein chains: 4

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Tubulin alpha-1B chain	A, C	451	Bos taurus	Mutation(s): 0 EC: 3.6.5
UniProt
Find proteins for P81947 (Bos taurus) Explore P81947 Go to UniProtKB: P81947
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P81947
Sequence Annotations Expand
Reference Sequence LOADING

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Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Tubulin beta-2B chain	B, D	445	Bos taurus	Mutation(s): 0
UniProt
Find proteins for Q6B856 (Bos taurus) Explore Q6B856 Go to UniProtKB: Q6B856
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q6B856
Sequence Annotations Expand
Reference Sequence LOADING

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Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Stathmin-4	E	143	Rattus norvegicus	Mutation(s): 0 Gene Names: Stmn4
UniProt
Find proteins for P63043 (Rattus norvegicus) Explore P63043 Go to UniProtKB: P63043
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P63043
Sequence Annotations Expand
Reference Sequence LOADING

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Entity ID: 4
Molecule	Chains	Sequence Length	Organism	Details	Image
Uncharacterized protein	F	384	Gallus gallus	Mutation(s): 0 Gene Names: TTL
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
GTP Query on GTP Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain L [auth C] MOL2 format, chain G [auth A] MOL2 format, chain L [auth C] mmCIF format, chain G [auth A] mmCIF format, chain L [auth C]	G [auth A], L [auth C]	GUANOSINE-5'-TRIPHOSPHATE C₁₀ H₁₆ N₅ O₁₄ P₃ XKMLYUALXHKNFT-UUOKFMHZSA-N		Interactions Focus chain G [auth A] Focus chain L [auth C] Interactions & Density Focus chain G [auth A] Focus chain L [auth C]
ACP Query on ACP Download Ideal Coordinates CCD File SDF format, chain Q [auth F] MOL2 format, chain Q [auth F] mmCIF format, chain Q [auth F]	Q [auth F]	PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER C₁₁ H₁₈ N₅ O₁₂ P₃ UFZTZBNSLXELAL-IOSLPCCCSA-N		Interactions Focus chain Q [auth F] Interactions & Density Focus chain Q [auth F]
GDP Query on GDP Download Ideal Coordinates CCD File SDF format, chain H [auth B] SDF format, chain M [auth D] MOL2 format, chain H [auth B] MOL2 format, chain M [auth D] mmCIF format, chain H [auth B] mmCIF format, chain M [auth D]	H [auth B], M [auth D]	GUANOSINE-5'-DIPHOSPHATE C₁₀ H₁₅ N₅ O₁₁ P₂ QGWNDRXFNXRZMB-UUOKFMHZSA-N		Interactions Focus chain H [auth B] Focus chain M [auth D] Interactions & Density Focus chain H [auth B] Focus chain M [auth D]
9N5 Query on 9N5 Download Ideal Coordinates CCD File SDF format, chain K [auth B] SDF format, chain P [auth D] MOL2 format, chain K [auth B] MOL2 format, chain P [auth D] mmCIF format, chain K [auth B] mmCIF format, chain P [auth D]	K [auth B], P [auth D]	(2~{R})-2-(3-ethynylquinolin-6-yl)oxy-2-methoxy-~{N}-[(1~{E})-1-methoxyimino-2-methyl-propan-2-yl]ethanamide C₁₉ H₂₁ N₃ O₄ PCSOIAVOYXKQKF-AGKWGAAGSA-N		Interactions Focus chain K [auth B] Focus chain P [auth D] Interactions & Density Focus chain K [auth B] Focus chain P [auth D]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain N [auth D] SDF format, chain O [auth D] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain N [auth D] MOL2 format, chain O [auth D] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain N [auth D] mmCIF format, chain O [auth D]	I [auth B], J [auth B], N [auth D], O [auth D]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain I [auth B] Focus chain J [auth B] Focus chain N [auth D] Focus chain O [auth D] Interactions & Density Focus chain I [auth B] Focus chain J [auth B] Focus chain N [auth D] Focus chain O [auth D]