title: Growth hormone receptor: structure function relationships.
abstract: BACKGROUND
  The growth hormone receptor (GHR) was the first class 1 cytokine receptor to be cloned, and it has been studied intensively. The crystal structures of the bound and unbound forms have been solved and the energetic contributions of residues involved in the binding interaction have been quantified. Two receptor subunits bind to opposite sides of the hormone through site 1 and site 2, and a third interaction occurs between receptors in the lower β-sandwich module at site 3. All three interactions are required for receptor activation, which was thought to be a consequence of hormone-induced receptor dimerization. However, substantial data support the existence of a constitutive receptor dimer that interacts via the transmembrane domain (TMD), with receptor activation triggered by a hormone-induced conformational change. Mutagenesis studies and crystal structure data indicate that receptor activation involves a relative rotation and scissor movement of subunits to activate the associated tyrosine kinase, Janus kinase 2 (JAK2). We have recently reported that a second tyrosine kinase, an Src-family kinase, also associates constitutively with the receptor and activates the Ras-extracellular-signal-regulated kinase pathway. Activation of this kinase requires a conformational change in a loop of the lower sandwich module, and a different orientation of the TMDs than needed for JAK2 activation.
  
  
  CONCLUSIONS
  This structural difference could allow differential activation of these two kinases by GH analogues such as I179M human GH.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Qld., Australia. m.waters @ imb.uq.eddu.au
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waters
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brooks
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011986:Receptors, Somatotropin / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D011986:Receptors, Somatotropin; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases