6BL8

Predicting the Conformational Variability of Abl Tyrosine Kinase Using Molecular Dynamics Simulations and Markov State Models

  • Classification: TRANSFERASE
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli
  • Mutation(s): No 

  • Deposited: 2017-11-09 Released: 2018-03-07 
  • Deposition Author(s): Clawson, D.K., Gao, C.
  • Funding Organization(s): National Institutes of Health/National Cancer Institute (NIH/NCI), Computation Institute and the Biological Sciences Division of the University of Chicago and Argonne National Laboratory (NIH), Extreme Science and Engineering Discovery Environment (XSEDE)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models.

Meng, Y.Gao, C.Clawson, D.K.Atwell, S.Russell, M.Vieth, M.Roux, B.

(2018) J Chem Theory Comput 14: 2721-2732

  • DOI: https://doi.org/10.1021/acs.jctc.7b01170
  • Primary Citation of Related Structures:  
    6BL8

  • PubMed Abstract: 

    Understanding protein conformational variability remains a challenge in drug discovery. The issue arises in protein kinases, whose multiple conformational states can affect the binding of small-molecule inhibitors. To overcome this challenge, we propose a comprehensive computational framework based on Markov state models (MSMs). Our framework integrates the information from explicit-solvent molecular dynamics simulations to accurately rank-order the accessible conformational variants of a target protein. We tested the methodology using Abl kinase with a reference and blind-test set. Only half of the Abl conformational variants discovered by our approach are present in the disclosed X-ray structures. The approach successfully identified a protein conformational state not previously observed in public structures but evident in a retrospective analysis of Lilly in-house structures: the X-ray structure of Abl with WHI-P154. Using a MSM-derived model, the free energy landscape and kinetic profile of Abl was analyzed in detail highlighting opportunities for targeting the unique metastable states.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology , University of Chicago , Chicago , Illinois 60637 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ABL1
A, B
272Homo sapiensMutation(s): 0 
Gene Names: ABL1ABLJTK7
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P00519 (Homo sapiens)
Explore P00519 
Go to UniProtKB:  P00519
PHAROS:  P00519
GTEx:  ENSG00000097007 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00519
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 105.84α = 90
b = 131.05β = 90
c = 57.02γ = 90
Software Package:
Software NamePurpose
MOSFLMdata collection
SCALAdata scaling
BUSTERrefinement
PDB_EXTRACTdata extraction
autoPROCdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesR01-CAO93577
Computation Institute and the Biological Sciences Division of the University of Chicago and Argonne National Laboratory (NIH)United StatesS10 RR029030-01
Extreme Science and Engineering Discovery Environment (XSEDE)United StatesOCI-1053575

Revision History  (Full details and data files)

  • Version 1.0: 2018-03-07
    Type: Initial release
  • Version 1.1: 2018-05-16
    Changes: Data collection, Database references
  • Version 1.2: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references, Refinement description