title: Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity.
abstract: The cytokine TGF-β modulates a number of cellular activities and plays a critical role in development, hemostasis and physiology, as well as in diseases including cancer and fibrosis. TGF-β signals through two transmembrane serine/threonine kinase receptors: TGFβR1 and TGFβR2. Multiple structures of the TGFβR1 kinase domain are known, but the structure of TGFβR2 remains unreported. Wild-type TGFβR2 kinase domain was refractory to crystallization, leading to the design of two mutated constructs: firstly, a TGFβR1 chimeric protein with seven ATP-site residues mutated to their counterparts in TGFβR2, and secondly, a reduction of surface entropy through mutation of six charged residues on the surface of the TGFβR2 kinase domain to alanines. These yielded apo and inhibitor-bound crystals that diffracted to high resolution (<2 Å). Comparison of these structures with those of TGFβR1 reveal shared ligand contacts as well as differences in the ATP-binding sites, suggesting strategies for the design of pan and selective TGFβR inhibitors.
authors.affiliation: Molecular Structure and Design, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.affiliation: Molecular Structure and Design, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Maxim
authors.initials: M
authors.lastname: Ruzanov
authors.affiliation: Protein Science, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Mian
authors.initials: M
authors.lastname: Gao
authors.affiliation: Protein Science, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Dianlin
authors.initials: D
authors.lastname: Xie
authors.affiliation: Protein Science, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Kiefer
authors.affiliation: Protein Science, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Yan
authors.affiliation: Protein Science, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.affiliation: Discovery Chemistry Oncology, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Discovery Chemistry Oncology, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Kyoung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Mechanistic Biochemistry, Bristol-Myers Squibb R & D, 311 Pennington Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Lu
authors.affiliation: Mechanistic Biochemistry, Bristol-Myers Squibb R & D, 311 Pennington Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kopcho
authors.affiliation: Molecular Structure and Design, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: TGFβR1 and TGFβR2 isoform selectivity; TGFβR2 kinase domain; apo and inhibitor-bound structures