4ASD

Crystal Structure of VEGFR2 (Juxtamembrane and Kinase Domains) in Complex with SORAFENIB (BAY 43-9006)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Molecular Conformations, Interactions, and Properties Associated with Drug Efficiency and Clinical Performance Among Vegfr Tk Inhibitors.

McTigue, M.Murray, B.W.Chen, J.H.Deng, Y.Solowiej, J.Kania, R.S.

(2012) Proc Natl Acad Sci U S A 109: 18281

  • DOI: https://doi.org/10.1073/pnas.1207759109
  • Primary Citation of Related Structures:  
    4AG8, 4AGC, 4AGD, 4ASD, 4ASE

  • PubMed Abstract: 

    Analyses of compounds in clinical development have shown that ligand efficient-molecules with privileged physical properties and low dose are less likely to fail in the various stages of clinical testing, have fewer postapproval withdrawals, and are less likely to receive black box safety warnings. However, detailed side-by-side examination of molecular interactions and properties within single drug classes are lacking. As a class, VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) have changed the landscape of how cancer is treated, particularly in clear cell renal cell carcinoma, which is molecularly linked to the VEGF signaling axis. Despite the clear role of the molecular target, member molecules of this validated drug class exhibit distinct clinical efficacy and safety profiles in comparable renal cell carcinoma clinical studies. The first head-to-head randomized phase III comparative study between active VEGFR TKIs has confirmed significant differences in clinical performance [Rini BI, et al. (2011) Lancet 378:193-1939]. To elucidate how fundamental drug potency-efficiency is achieved and impacts differentiation within the VEGFR TKI class, we determined potencies, time dependence, selectivities, and X-ray structures of the drug-kinase complexes using a VEGFR2 TK construct inclusive of the important juxtamembrane domain. Collectively, the studies elucidate unique drug-kinase interactions that are dependent on distinct juxtamembrane domain conformations, resulting in significant potency and ligand efficiency differences. The identified structural trends are consistent with in vitro measurements, which translate well to clinical performance, underscoring a principle that may be broadly applicable to prospective drug design for optimal in vivo performance.


  • Organizational Affiliation

    Department of Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, Pfizer Inc., San Diego, CA 92121, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2353Homo sapiensMutation(s): 1 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P35968 (Homo sapiens)
Explore P35968 
Go to UniProtKB:  P35968
PHAROS:  P35968
GTEx:  ENSG00000128052 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35968
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BAX
Query on BAX

Download Ideal Coordinates CCD File 
B [auth A]4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE
C21 H16 Cl F3 N4 O3
MLDQJTXFUGDVEO-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BAX BindingDB:  4ASD Ki: min: 0.02, max: 22 (nM) from 3 assay(s)
Kd: min: 33, max: 93 (nM) from 3 assay(s)
IC50: min: 0.16, max: 1210 (nM) from 44 assay(s)
EC50: 500 (nM) from 1 assay(s)
Binding MOAD:  4ASD Ki: 0.52 (nM) from 1 assay(s)
PDBBind:  4ASD Ki: 0.52 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 135.818α = 90
b = 56.479β = 95.42
c = 52.052γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CCP4phasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-09-26
    Type: Initial release
  • Version 1.1: 2012-10-03
    Changes: Non-polymer description
  • Version 1.2: 2012-11-14
    Changes: Database references
  • Version 1.3: 2018-05-23
    Changes: Data collection, Database references, Structure summary
  • Version 1.4: 2019-05-08
    Changes: Data collection, Experimental preparation
  • Version 1.5: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Refinement description