Structure of the Human Anaplastic Lymphoma Kinase in Complex with Crizotinib (PF-02341066)

Structure Based Drug Design of Crizotinib (Pf-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (C-met) Kinase and Anaplastic Lymphoma Kinase (Alk).

TYROSINE KINASE DOMAIN, RESIDUES 105-423

MAHHHHHHNPNYCFAGKTSSISDLKEVPRKNITLIRGLGHGAFGEVYEGQVSGMPNDPSPLQVAVKTLPEVCSEQDELDF
LMEALIISKFNHQNIVRCIGVSLQSLPRFILLELMAGGDLKSFLRETRPRPSQPSSLAMLDLLHVARDIACGCQYLEENH
FIHRDIAARNCLLTCPGPGRVAKIGDFGMARDIYRASYYRKGGCAMLPVKWMPPEAFMEGIFTSKTDTWSFGVLLWEIFS
LGYMPYPSKSNQEVLEFVTSGGRMDPPKNCPGPVYRIMTQCWQHQPEDRPNFAIILERIEYCTQDPDVINTALPIEYGPL
VEEEEKV

CO-CRYSTALS OF ALK KINASE DOMAIN WITH PF-02341066 WERE OBTAINED AT 13 DEGREES C BY USING HANGING-DROP VAPOR-DIFFUSION. 0.5 MICROLITERS OF 1:3 MOLAR RATIO OF 14.9 MG/ML PROTEIN SOLUTION TO PF02341066 WAS MIXED WITH 0.5 MICROLITERS OF RESERVOIR SOLUTION CONTAINING 7-10% (W/V) MEPEG 5K, 0.1M MES, PH6.0-6.5 AND 0.15M (NH4)2SO4.