5MJB

Kinase domain of human EphB1, G703C mutant, covalently bound to a quinazoline-based inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.199 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A Chemical-Genetic Approach to Generate Selective Covalent Inhibitors of Protein Kinases.

Kung, A.Schimpl, M.Ekanayake, A.Chen, Y.C.Overman, R.Zhang, C.

(2017) ACS Chem Biol 12: 1499-1503

  • DOI: https://doi.org/10.1021/acschembio.6b01083
  • Primary Citation of Related Structures:  
    5MJA, 5MJB

  • PubMed Abstract: 

    Although a previously developed bump-hole approach has proven powerful in generating specific inhibitors for mapping functions of protein kinases, its application is limited by the intolerance of the large-to-small mutation by certain kinases and the inability to control two kinases separately in the same cells. Herein, we describe the development of an alternative chemical-genetic approach to overcome these limitations. Our approach features the use of an engineered cysteine residue at a particular position as a reactive feature to sensitize a kinase of interest to selective covalent blockade by electrophilic inhibitors and is thus termed the Ele-Cys approach. We successfully applied the Ele-Cys approach to identify selective covalent inhibitors of a receptor tyrosine kinase EphB1 and solved cocrystal structures to determine the mode of covalent binding. Importantly, the Ele-Cys and bump-hole approaches afforded orthogonal inhibition of two distinct kinases in the cell, opening the door to their combined use in the study of multikinase signaling pathways.


  • Organizational Affiliation

    Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Building 310, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ephrin type-B receptor 1
A, B
305Homo sapiensMutation(s): 0 
Gene Names: EPHB1ELKEPHT2HEK6NET
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P54762 (Homo sapiens)
Explore P54762 
Go to UniProtKB:  P54762
PHAROS:  P54762
GTEx:  ENSG00000154928 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP54762
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.199 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.2α = 90
b = 102.2β = 90
c = 157.55γ = 120
Software Package:
Software NamePurpose
BUSTERrefinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-17
    Type: Initial release
  • Version 1.1: 2017-06-28
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description