5LXT

Tubulin-Discodermolide complex

PDB DOI: https://doi.org/10.2210/pdb5LXT/pdb

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

Deposited: 2016-09-22 Released: 2017-03-01
Deposition Author(s): Prota, A.E., Steinmetz, M.O.
Funding Organization(s): Swiss National Science Foundation, Spanish Ministry of Economy and Competitiveness, National Institutes of Health/National Cancer Institute (NIH/NCI), Breast Cancer Research Foundation

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.90 ?
R-Value Free: 0.208
R-Value Work: 0.173
R-Value Observed: 0.175

Starting Model: 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

Structural Basis of Microtubule Stabilization by Discodermolide.

Prota, A.E., Bargsten, K., Redondo-Horcajo, M., Smith, A.B., Yang, C.H., McDaid, H.M., Paterson, I., Horwitz, S.B., Fernando Diaz, J., Steinmetz, M.O.

(2017) Chembiochem 18: 905-909

PubMed: 28207984 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/cbic.201600696
Primary Citation of Related Structures:
5LXS, 5LXT

PubMed Abstract:
Microtubule-stabilizing agents (MSAs) are widely used in chemotherapy. Using X-ray crystallography we elucidated the detailed binding modes of two potent MSAs, (+)-discodermolide (DDM) and the DDM-paclitaxel hybrid KS-1-199-32, in the taxane pocket of β-tubulin. The two compounds bind in a very similar hairpin conformation, as previously observed in solution. However, they stabilize the M-loop of β-tubulin differently: KS-1-199-32 induces an M-loop helical conformation that is not observed for DDM. In the context of the microtubule structure, both MSAs connect the β-tubulin helices H6 and H7 and loop S9-S10 with the M-loop. This is similar to the structural effects elicited by epothilone?A, but distinct from paclitaxel. Together, our data reveal differential binding mechanisms of DDM and KS-1-199-32 on tubulin.

Organizational Affiliation

Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.

Macromolecule Content

Total Structure Weight: 265.73 kDa
Atom Count: 19,585
Modelled Residue Count: 2,210
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 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

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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 Gene Names: TTL
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
7AK Query on 7AK Download Ideal Coordinates CCD File SDF format, chain O [auth B] SDF format, chain U [auth D] MOL2 format, chain O [auth B] MOL2 format, chain U [auth D] mmCIF format, chain O [auth B] mmCIF format, chain U [auth D]	O [auth B], U [auth D]	(+)-Discodermolide C₃₃ H₅₅ N O₈ AADVCYNFEREWOS-OBRABYBLSA-N		Interactions Focus chain O [auth B] Focus chain U [auth D] Interactions & Density Focus chain O [auth B] Focus chain U [auth D]
GTP Query on GTP Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain P [auth C] MOL2 format, chain G [auth A] MOL2 format, chain P [auth C] mmCIF format, chain G [auth A] mmCIF format, chain P [auth C]	G [auth A], P [auth C]	GUANOSINE-5'-TRIPHOSPHATE C₁₀ H₁₆ N₅ O₁₄ P₃ XKMLYUALXHKNFT-UUOKFMHZSA-N		Interactions Focus chain G [auth A] Focus chain P [auth C] Interactions & Density Focus chain G [auth A] Focus chain P [auth C]
ACP Query on ACP Download Ideal Coordinates CCD File SDF format, chain V [auth F] MOL2 format, chain V [auth F] mmCIF format, chain V [auth F]	V [auth F]	PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER C₁₁ H₁₈ N₅ O₁₂ P₃ UFZTZBNSLXELAL-IOSLPCCCSA-N		Interactions Focus chain V [auth F] Interactions & Density Focus chain V [auth F]
GDP Query on GDP Download Ideal Coordinates CCD File SDF format, chain K [auth B] SDF format, chain S [auth D] MOL2 format, chain K [auth B] MOL2 format, chain S [auth D] mmCIF format, chain K [auth B] mmCIF format, chain S [auth D]	K [auth B], S [auth D]	GUANOSINE-5'-DIPHOSPHATE C₁₀ H₁₅ N₅ O₁₁ P₂ QGWNDRXFNXRZMB-UUOKFMHZSA-N		Interactions Focus chain K [auth B] Focus chain S [auth D] Interactions & Density Focus chain K [auth B] Focus chain S [auth D]
MES Query on MES Download Ideal Coordinates CCD File SDF format, chain N [auth B] MOL2 format, chain N [auth B] mmCIF format, chain N [auth B]	N [auth B]	2-(N-MORPHOLINO)-ETHANESULFONIC ACID C₆ H₁₃ N O₄ S SXGZJKUKBWWHRA-UHFFFAOYSA-N		Interactions Focus chain N [auth B] Interactions & Density Focus chain N [auth B]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain R [auth C] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain M [auth B] MOL2 format, chain R [auth C] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain M [auth B] mmCIF format, chain R [auth C] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain M [auth B]	I [auth A], J [auth A], M [auth B], R [auth C]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Focus chain R [auth C] Interactions & Density Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Focus chain R [auth C]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain Q [auth C] SDF format, chain H [auth A] SDF format, chain L [auth B] SDF format, chain T [auth D] SDF format, chain W [auth F] MOL2 format, chain Q [auth C] MOL2 format, chain H [auth A] MOL2 format, chain L [auth B] MOL2 format, chain T [auth D] MOL2 format, chain W [auth F] mmCIF format, chain Q [auth C] mmCIF format, chain H [auth A] mmCIF format, chain L [auth B] mmCIF format, chain T [auth D] mmCIF format, chain W [auth F]	H [auth A], L [auth B], Q [auth C], T [auth D], W [auth F]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain L [auth B] Focus chain Q [auth C] Focus chain T [auth D] Focus chain W [auth F] Interactions & Density Focus chain H [auth A] Focus chain L [auth B] Focus chain Q [auth C] Focus chain T [auth D] Focus chain W [auth F]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.90 ?
R-Value Free: 0.208
R-Value Work: 0.173
R-Value Observed: 0.175
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 104.5	α = 90
b = 157.79	β = 90
c = 180.23	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data reduction
XSCALE	data scaling
PHENIX	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2017-03-01

Deposition Author(s):

Prota, A.E.

Steinmetz, M.O.

Funding Organization	Location	Grant Number
Swiss National Science Foundation	Switzerland	310030B_138659 and 31003A_166608
Spanish Ministry of Economy and Competitiveness	Spain	BIO2013-42984-R and S2010/BMD-2457 BIPEDD2
National Institutes of Health/National Cancer Institute (NIH/NCI)	United States	CA077263
Breast Cancer Research Foundation	United States	--

Revision History (Full details and data files)

Version 1.0: 2017-03-01
Type: Initial release
Version 1.1: 2017-06-07
Changes: Database references
Version 1.2: 2017-09-13
Changes: Author supporting evidence
Version 1.3: 2022-03-30
Changes: Author supporting evidence, Database references, Derived calculations
Version 1.4: 2024-01-17
Changes: Data collection, Refinement description