title: Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK).
abstract: Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, αC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure-activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.|Institute of Bioinformatics and Structural Biology, National Tsing Hua University , 101, Sect. 2, Guangfu Road, Hsinchu 300, Taiwan, ROC.
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Tu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Peng
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Tsu
authors.initials: T
authors.lastname: Hsu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Cheng-Tai
authors.initials: CT
authors.lastname: Lu
authors.affiliation: Institute of Bioinformatics and Structural Biology, National Tsing Hua University , 101, Sect. 2, Guangfu Road, Hsinchu 300, Taiwan, ROC.
authors.forename: Ping-Chiang
authors.initials: PC
authors.lastname: Lyu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases