PDBsum entry 4ag8

Transferase

PDB id: 4ag8

Contents

Protein chain

296 a.a.

Ligands

AXI

Waters ×326

PDB id:

4ag8

Name:

Transferase

Title:

Crystal structure of the vegfr2 kinase domain in complex with axitinib (ag-013736) (n-methyl-2-(3-((e)-2-pyridin-2-yl-vinyl)-1h- indazol-6- ylsulfanyl)-benzamide)

Structure:

Vascular endothelial growth factor receptor 2. Chain: a. Fragment: kinase domain, residues 806-940,990-1171. Synonym: vegfr-2, fetal liver kinase 1, flk-1, kinase insert domain receptor, kdr, protein-tyrosine kinase receptor flk-1, cd309. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.95Å R-factor: 0.197 R-free: 0.242

Authors:

M.Mctigue,J.Wickersham,C.Pinko,R.S.Kania,S.Bender

Key ref:

M.McTigue et al. (2012). Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Natl Acad Sci U S A, 109, 18281-18289. PubMed id: 22988103

Date:

24-Jan-12 Release date: 26-Sep-12

Protein chain

P35968  (VGFR2_HUMAN) -  Vascular endothelial growth factor receptor 2 from Homo sapiens

Seq: 1356 a.a.

Struc: 296 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

Proc Natl Acad Sci U S A 109:18281-18289 (2012)

PubMed id: 22988103

Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors.

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

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.