4I4T

Crystal structure of tubulin-RB3-TTL-Zampanolide complex

PDB DOI: https://doi.org/10.2210/pdb4I4T/pdb

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

Deposited: 2012-11-28 Released: 2013-01-23
Deposition Author(s): Prota, A.E., Steinmetz, M.O.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.204
R-Value Work: 0.171
R-Value Observed: 0.173

Starting Models: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents.

Prota, A.E., Bargsten, K., Zurwerra, D., Field, J.J., Diaz, J.F., Altmann, K.H., Steinmetz, M.O.

(2013) Science 339: 587-590

PubMed: 23287720 Search on PubMed
DOI: https://doi.org/10.1126/science.1230582
Primary Citation of Related Structures:
4I4T, 4I50, 4I55

PubMed Abstract:
Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. We determined high-resolution crystal structures of αβ-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane pocket of β-tubulin and used their respective side chains to induce structuring of the M-loop into a short helix. Because the M-loop establishes lateral tubulin contacts in microtubules, these findings explain how taxane-site MSAs promote microtubule assembly and stability. Further, our results offer fundamental structural insights into the control mechanisms of microtubule dynamics.

Organizational Affiliation

Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland.

Macromolecule Content

Total Structure Weight: 265.6 kDa
Atom Count: 19,745
Modelled Residue Count: 2,218
Deposited Residue Count: 2,317
Unique protein chains: 4

Macromolecules

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Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Tubulin alpha-1B chain	A, C	450	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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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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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
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Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 4
Molecule	Chains	Sequence Length	Organism	Details	Image
Tubulin Tyrosine ligase, TTL	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

Small Molecules

Ligands 10 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 V [auth C] MOL2 format, chain G [auth A] MOL2 format, chain V [auth C] mmCIF format, chain G [auth A] mmCIF format, chain V [auth C]	G [auth A], V [auth C]	GUANOSINE-5'-TRIPHOSPHATE C₁₀ H₁₆ N₅ O₁₄ P₃ XKMLYUALXHKNFT-UUOKFMHZSA-N		Interactions Focus chain G [auth A] Focus chain V [auth C] Interactions & Density Focus chain G [auth A] Focus chain V [auth C]
ACP Query on ACP Download Ideal Coordinates CCD File SDF format, chain DA [auth F] MOL2 format, chain DA [auth F] mmCIF format, chain DA [auth F]	DA [auth F]	PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER C₁₁ H₁₈ N₅ O₁₂ P₃ UFZTZBNSLXELAL-IOSLPCCCSA-N		Interactions Focus chain DA [auth F] Interactions & Density Focus chain DA [auth F]
ZPN Query on ZPN Download Ideal Coordinates CCD File SDF format, chain AA [auth D] MOL2 format, chain AA [auth D] mmCIF format, chain AA [auth D]	AA [auth D]	(2Z,4E)-N-[(S)-[(1S,2E,5S,8E,10Z,17S)-3,11-dimethyl-19-methylidene-7,13-dioxo-6,21-dioxabicyclo[15.3.1]henicosa-2,8,10-trien-5-yl](hydroxy)methyl]hexa-2,4-dienamide C₂₉ H₃₉ N O₆ KNEMNZWQWFRUIB-KZVIXHMTSA-N		Interactions Focus chain AA [auth D] Interactions & Density Focus chain AA [auth D]
GDP Query on GDP Download Ideal Coordinates CCD File SDF format, chain O [auth B] SDF format, chain Y [auth D] MOL2 format, chain O [auth B] MOL2 format, chain Y [auth D] mmCIF format, chain O [auth B] mmCIF format, chain Y [auth D]	O [auth B], Y [auth D]	GUANOSINE-5'-DIPHOSPHATE C₁₀ H₁₅ N₅ O₁₁ P₂ QGWNDRXFNXRZMB-UUOKFMHZSA-N		Interactions Focus chain O [auth B] Focus chain Y [auth D] Interactions & Density Focus chain O [auth B] Focus chain Y [auth D]
MES Query on MES Download Ideal Coordinates CCD File SDF format, chain U [auth B] MOL2 format, chain U [auth B] mmCIF format, chain U [auth B]	U [auth B]	2-(N-MORPHOLINO)-ETHANESULFONIC ACID C₆ H₁₃ N O₄ S SXGZJKUKBWWHRA-UHFFFAOYSA-N		Interactions Focus chain U [auth B] Interactions & Density Focus chain U [auth B]
TYR Query on TYR Download Ideal Coordinates CCD File SDF format, chain T [auth B] MOL2 format, chain T [auth B] mmCIF format, chain T [auth B]	T [auth B]	TYROSINE C₉ H₁₁ N O₃ OUYCCCASQSFEME-QMMMGPOBSA-N		Interactions Focus chain T [auth B] Interactions & Density Focus chain T [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain EA [auth F] SDF format, chain FA [auth F] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain R [auth B] SDF format, chain S [auth B] MOL2 format, chain EA [auth F] MOL2 format, chain FA [auth F] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] mmCIF format, chain EA [auth F] mmCIF format, chain FA [auth F] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B]	EA [auth F] FA [auth F] L [auth A] M [auth A] N [auth A] EA [auth F], FA [auth F], L [auth A], M [auth A], N [auth A], R [auth B], S [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain EA [auth F] Focus chain FA [auth F] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain R [auth B] Focus chain S [auth B] Interactions & Density Focus chain EA [auth F] Focus chain FA [auth F] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain R [auth B] Focus chain S [auth B]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain Q [auth B] SDF format, chain X [auth C] SDF format, chain I [auth A] MOL2 format, chain K [auth A] MOL2 format, chain Q [auth B] MOL2 format, chain X [auth C] MOL2 format, chain I [auth A] mmCIF format, chain K [auth A] mmCIF format, chain Q [auth B] mmCIF format, chain X [auth C] mmCIF format, chain I [auth A]	I [auth A], K [auth A], Q [auth B], X [auth C]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain K [auth A] Focus chain Q [auth B] Focus chain X [auth C] Interactions & Density Focus chain I [auth A] Focus chain K [auth A] Focus chain Q [auth B] Focus chain X [auth C]
CL Query on CL 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]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain J [auth A] Interactions & Density Focus chain J [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain BA [auth F] SDF format, chain CA [auth F] SDF format, chain H [auth A] SDF format, chain P [auth B] SDF format, chain W [auth C] SDF format, chain Z [auth D] MOL2 format, chain BA [auth F] MOL2 format, chain CA [auth F] MOL2 format, chain H [auth A] MOL2 format, chain P [auth B] MOL2 format, chain W [auth C] MOL2 format, chain Z [auth D] mmCIF format, chain BA [auth F] mmCIF format, chain CA [auth F] mmCIF format, chain H [auth A] mmCIF format, chain P [auth B] mmCIF format, chain W [auth C] mmCIF format, chain Z [auth D]	BA [auth F] CA [auth F] H [auth A] P [auth B] W [auth C] BA [auth F], CA [auth F], H [auth A], P [auth B], W [auth C], Z [auth D]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain BA [auth F] Focus chain CA [auth F] Focus chain H [auth A] Focus chain P [auth B] Focus chain W [auth C] Focus chain Z [auth D] Interactions & Density Focus chain BA [auth F] Focus chain CA [auth F] Focus chain H [auth A] Focus chain P [auth B] Focus chain W [auth C] Focus chain Z [auth D]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.204
R-Value Work: 0.171
R-Value Observed: 0.173
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 104.77	α = 90
b = 158.64	β = 90
c = 179.24	γ = 90

Software Package:

Software Name	Purpose
RemDAq	data collection
PHASER	phasing
PHENIX	refinement
XDS	data reduction
XDS	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-01-23

Deposition Author(s):

Prota, A.E.

Steinmetz, M.O.

Revision History (Full details and data files)

Version 1.0: 2013-01-23
Type: Initial release
Version 1.1: 2013-02-13
Changes: Database references
Version 1.2: 2013-02-20
Changes: Database references
Version 1.3: 2017-11-15
Changes: Refinement description
Version 1.4: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description

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Help and Resources

4I4T

Crystal structure of tubulin-RB3-TTL-Zampanolide complex

Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents.

Entity ID: 1

UniProt

Entity Groups

Sequence Annotations

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Entity ID: 2

UniProt

Entity Groups

Sequence Annotations

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Entity ID: 3

UniProt

Entity Groups

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Entity ID: 4

Entity Groups

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)