7Z7D

Tubulin-Todalam-Vinblastine-complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action.

Muhlethaler, T.Milanos, L.Ortega, J.A.Blum, T.B.Gioia, D.Roy, B.Prota, A.E.Cavalli, A.Steinmetz, M.O.

(2022) Angew Chem Int Ed Engl 61: e202204052-e202204052

  • DOI: https://doi.org/10.1002/anie.202204052
  • Primary Citation of Related Structures:  
    5SB3, 5SB4, 5SB5, 5SB6, 5SB7, 7Z7D

  • PubMed Abstract: 

    In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the α-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers. Our results describe for the first time the generation of a fully rationally designed small molecule tubulin inhibitor from a fragment, which displays a unique molecular mechanism of action. They thus demonstrate the usefulness of tubulin-binding fragments as valuable starting points for innovative antitubulin drug and chemical probe discovery campaigns.


  • Organizational Affiliation

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


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tubulin alpha-1B chain
A, C
451Bos taurusMutation(s): 0 
EC: 3.6.5
UniProt
Find proteins for P81947 (Bos taurus)
Explore P81947 
Go to UniProtKB:  P81947
Entity Groups  
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UniProt GroupP81947
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Tubulin beta-2B chain
B, D
445Bos taurusMutation(s): 0 
UniProt
Find proteins for Q6B856 (Bos taurus)
Explore Q6B856 
Go to UniProtKB:  Q6B856
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UniProt GroupQ6B856
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Stathmin-4143Rattus norvegicusMutation(s): 0 
Gene Names: Stmn4
UniProt
Find proteins for P63043 (Rattus norvegicus)
Explore P63043 
Go to UniProtKB:  P63043
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UniProt GroupP63043
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Tubulin beta-2B chain384Gallus gallusMutation(s): 0 
Gene Names: TTL
Entity Groups  
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  • Reference Sequence
Small Molecules
Ligands 8 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
VLB (Subject of Investigation/LOI)
Query on VLB

Download Ideal Coordinates CCD File 
N [auth B](2ALPHA,2'BETA,3BETA,4ALPHA,5BETA)-VINCALEUKOBLASTINE
C46 H58 N4 O9
JXLYSJRDGCGARV-CFWMRBGOSA-N
GTP
Query on GTP

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G [auth A],
O [auth C]
GUANOSINE-5'-TRIPHOSPHATE
C10 H16 N5 O14 P3
XKMLYUALXHKNFT-UUOKFMHZSA-N
ACP
Query on ACP

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V [auth F]PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER
C11 H18 N5 O12 P3
UFZTZBNSLXELAL-IOSLPCCCSA-N
GDP
Query on GDP

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J [auth B],
S [auth D]
GUANOSINE-5'-DIPHOSPHATE
C10 H15 N5 O11 P2
QGWNDRXFNXRZMB-UUOKFMHZSA-N
4I2 (Subject of Investigation/LOI)
Query on 4I2

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R [auth C]N-(4-{2-[3-(trifluoromethyl)anilino]-1,3-thiazol-4-yl}phenyl)acetamide
C18 H14 F3 N3 O S
WCPMDFWXUJATQO-UHFFFAOYSA-N
MES
Query on MES

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M [auth B]2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
CA
Query on CA

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I [auth A],
L [auth B],
Q [auth C],
U [auth E]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
MG
Query on MG

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H [auth A],
K [auth B],
P [auth C],
T [auth D],
W [auth F]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 105.286α = 90
b = 157.296β = 90
c = 182.526γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Union (EU)European UnionID239047 NEON
Swiss National Science FoundationSwitzerland31003A_166608
Swiss National Science FoundationSwitzerland310030_192566

Revision History  (Full details and data files)

  • Version 1.0: 2022-04-27
    Type: Initial release
  • Version 1.1: 2022-05-04
    Changes: Database references
  • Version 1.2: 2022-06-22
    Changes: Database references
  • Version 1.3: 2024-01-31
    Changes: Data collection, Refinement description