4O4J

Tubulin-Peloruside A complex

PDB DOI: https://doi.org/10.2210/pdb4O4J/pdb

Classification: CELL CYCLE/INHIBITOR
Organism(s): Bos taurus, Rattus norvegicus, Gallus gallus
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2013-12-18 Released: 2014-03-26
Deposition Author(s): Prota, A.E., Bargsten, K., Northcote, P.T., Marsh, M., Altmann, K.H., Miller, J.H., Diaz, J.F., Steinmetz, M.O.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.20 ?
R-Value Free: 0.239
R-Value Work: 0.201
R-Value Observed: 0.203

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Structural basis of microtubule stabilization by laulimalide and peloruside A.

Prota, A.E., Bargsten, K., Northcote, P.T., Marsh, M., Altmann, K.H., Miller, J.H., Diaz, J.F., Steinmetz, M.O.

(2014) Angew Chem Int Ed Engl 53: 1621-1625

PubMed: 24470331 Search on PubMed
DOI: https://doi.org/10.1002/anie.201307749
Primary Citation of Related Structures:
4O4H, 4O4I, 4O4J, 4O4L

PubMed Abstract:
Laulimalide and peloruside?A are microtubule-stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X-ray crystallography it is shown that laulimalide and peloruside?A bind to a unique non-taxane site on β-tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane-site M-loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/peloruside?A and epothilone?A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M-loop of β-tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside?A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.

Organizational Affiliation

Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI (Switzerland).

Macromolecule Content

Total Structure Weight: 265.4 kDa
Atom Count: 18,124
Modelled Residue Count: 2,126
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

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(by identity cutoff) | 3D Structure

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

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(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Stathmin-4	E	143	Rattus norvegicus	Mutation(s): 0
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

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(by identity cutoff) | 3D Structure

Entity ID: 4
Molecule	Chains	Sequence Length	Organism	Details	Image
Tubulin-tyrosine ligase	F	384	Gallus gallus	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 7 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
POU Query on POU Download Ideal Coordinates CCD File SDF format, chain M [auth B] SDF format, chain R [auth D] MOL2 format, chain M [auth B] MOL2 format, chain R [auth D] mmCIF format, chain M [auth B] mmCIF format, chain R [auth D]	M [auth B], R [auth D]	Peloruside A C₂₇ H₄₈ O₁₁ NETARJWZTMGMRM-QOXVJYTGSA-N		Interactions Focus chain M [auth B] Focus chain R [auth D] Interactions & Density Focus chain M [auth B] Focus chain R [auth D]
GTP Query on GTP Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain N [auth C] MOL2 format, chain G [auth A] MOL2 format, chain N [auth C] mmCIF format, chain G [auth A] mmCIF format, chain N [auth C]	G [auth A], N [auth C]	GUANOSINE-5'-TRIPHOSPHATE C₁₀ H₁₆ N₅ O₁₄ P₃ XKMLYUALXHKNFT-UUOKFMHZSA-N		Interactions Focus chain G [auth A] Focus chain N [auth C] Interactions & Density Focus chain G [auth A] Focus chain N [auth C]
ACP Query on ACP Download Ideal Coordinates CCD File SDF format, chain S [auth F] MOL2 format, chain S [auth F] mmCIF format, chain S [auth F]	S [auth F]	PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER C₁₁ H₁₈ N₅ O₁₂ P₃ UFZTZBNSLXELAL-IOSLPCCCSA-N		Interactions Focus chain S [auth F] Interactions & Density Focus chain S [auth F]
GDP Query on GDP 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]	GUANOSINE-5'-DIPHOSPHATE C₁₀ H₁₅ N₅ O₁₁ P₂ QGWNDRXFNXRZMB-UUOKFMHZSA-N		Interactions Focus chain K [auth B] Focus chain P [auth D] Interactions & Density Focus chain K [auth B] Focus chain P [auth D]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain J [auth A] MOL2 format, chain J [auth A] mmCIF format, chain J [auth A]	J [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Interactions & Density Focus chain J [auth A]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A] mmCIF format, chain I [auth A]	I [auth A]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain L [auth B] SDF format, chain O [auth C] SDF format, chain Q [auth D] MOL2 format, chain H [auth A] MOL2 format, chain L [auth B] MOL2 format, chain O [auth C] MOL2 format, chain Q [auth D] mmCIF format, chain H [auth A] mmCIF format, chain L [auth B] mmCIF format, chain O [auth C] mmCIF format, chain Q [auth D]	H [auth A], L [auth B], O [auth C], Q [auth D]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain L [auth B] Focus chain O [auth C] Focus chain Q [auth D] Interactions & Density Focus chain H [auth A] Focus chain L [auth B] Focus chain O [auth C] Focus chain Q [auth D]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.20 ?
R-Value Free: 0.239
R-Value Work: 0.201
R-Value Observed: 0.203
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 104.37	α = 90
b = 157.84	β = 90
c = 180.36	γ = 90

Software Package:

Software Name	Purpose
DA+	data collection
PHENIX	model building
PHENIX	refinement
XDS	data reduction
XDS	data scaling
PHENIX	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-03-26

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2014-03-26
Type: Initial release
Version 1.1: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description