6I8L

Crystal structure of Spindlin1 in complex with the inhibitor TD001851a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.

Fagan, V.Johansson, C.Gileadi, C.Monteiro, O.Dunford, J.E.Nibhani, R.Philpott, M.Malzahn, J.Wells, G.Faram, R.Cribbs, A.P.Halidi, N.Li, F.Chau, I.Greschik, H.Velupillai, S.Allali-Hassani, A.Bennett, J.Christott, T.Giroud, C.Lewis, A.M.Huber, K.V.M.Athanasou, N.Bountra, C.Jung, M.Schule, R.Vedadi, M.Arrowsmith, C.Xiong, Y.Jin, J.Fedorov, O.Farnie, G.Brennan, P.E.Oppermann, U.

(2019) J Med Chem 62: 9008-9025

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00562
  • Primary Citation of Related Structures:  
    6I8B, 6I8L, 6I8Y

  • PubMed Abstract: 

    Modifications of histone tails, including lysine/arginine methylation, provide the basis of a "chromatin or histone code". Proteins that contain "reader" domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional coactivator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a role in cancer related inflammation and/or cancer metastasis.


  • Organizational Affiliation

    Structural Genomics Consortium, Nuffield Department of Medicine , University of Oxford , OX3 7DQ Oxford , U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Spindlin-1A [auth B]222Homo sapiensMutation(s): 0 
Gene Names: SPIN1OCRSPIN
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y657 (Homo sapiens)
Explore Q9Y657 
Go to UniProtKB:  Q9Y657
PHAROS:  Q9Y657
GTEx:  ENSG00000106723 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y657
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
H7Q
Query on H7Q

Download Ideal Coordinates CCD File 
E [auth B]5'-(cyclopropylmethoxy)-6'-[3-(1,3-dihydroisoindol-2-yl)propoxy]spiro[cyclopentane-1,3'-indole]-2'-amine
C27 H33 N3 O2
BHUFHRHQTFNIPQ-UHFFFAOYSA-N
MRD
Query on MRD

Download Ideal Coordinates CCD File 
C [auth B](4R)-2-METHYLPENTANE-2,4-DIOL
C6 H14 O2
SVTBMSDMJJWYQN-RXMQYKEDSA-N
MPD
Query on MPD

Download Ideal Coordinates CCD File 
B
(4S)-2-METHYL-2,4-PENTANEDIOL
C6 H14 O2
SVTBMSDMJJWYQN-YFKPBYRVSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
D [auth B]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
F [auth B]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 115.35α = 90
b = 115.35β = 90
c = 43.76γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-05
    Type: Initial release
  • Version 1.1: 2020-01-15
    Changes: Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description