4NUS

Rsk2 N-terminal kinase in complex with LJH685


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Novel potent and selective inhibitors of p90 ribosomal S6 kinase reveal the heterogeneity of RSK function in MAPK-driven cancers.

Aronchik, I.Appleton, B.A.Basham, S.E.Crawford, K.Del Rosario, M.Doyle, L.V.Estacio, W.F.Lan, J.Lindvall, M.K.Luu, C.A.Ornelas, E.Venetsanakos, E.Shafer, C.M.Jefferson, A.B.

(2014) Mol Cancer Res 12: 803-812

  • DOI: https://doi.org/10.1158/1541-7786.MCR-13-0595
  • Primary Citation of Related Structures:  
    4NUS

  • PubMed Abstract: 

    The p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases is expressed in a variety of cancers and its substrate phosphorylation has been implicated in direct regulation of cell survival, proliferation, and cell polarity. This study characterizes and presents the most selective and potent RSK inhibitors known to date, LJH685 and LJI308. Structural analysis confirms binding of LJH685 to the RSK2 N-terminal kinase ATP-binding site and reveals that the inhibitor adopts an unusual nonplanar conformation that explains its excellent selectivity for RSK family kinases. LJH685 and LJI308 efficiently inhibit RSK activity in vitro and in cells. Furthermore, cellular inhibition of RSK and its phosphorylation of YB1 on Ser102 correlate closely with inhibition of cell growth, but only in an anchorage-independent growth setting, and in a subset of examined cell lines. Thus, RSK inhibition reveals dynamic functional responses among the inhibitor-sensitive cell lines, underscoring the heterogeneous nature of RSK dependence in cancer.


  • Organizational Affiliation

    Authors' Affiliations: Novartis Institutes for BioMedical Research, Emeryville, California; and 2Shanghai Haiyan Pharmaceutical Technology Co., Ltd., Shanghai.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ribosomal protein S6 kinase alpha-3323Homo sapiensMutation(s): 0 
Gene Names: RPS6KA3ISPK1MAPKAPK1BRSK2
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P51812 (Homo sapiens)
Explore P51812 
Go to UniProtKB:  P51812
PHAROS:  P51812
GTEx:  ENSG00000177189 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51812
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2NK
Query on 2NK

Download Ideal Coordinates CCD File 
B [auth A]2,6-difluoro-4-{4-[4-(4-methylpiperazin-1-yl)phenyl]pyridin-3-yl}phenol
C22 H21 F2 N3 O
IKUFKDGKRLMXEX-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2NK BindingDB:  4NUS IC50: min: 5, max: 340 (nM) from 2 assay(s)
Binding MOAD:  4NUS IC50: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.271α = 90
b = 62.812β = 90
c = 117.244γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
PROCESSdata reduction
PROCESSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-03-05
    Type: Initial release
  • Version 1.1: 2014-11-12
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations