Your browser doesn't support javascript.
loading
Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases.
Sheetz, Joshua B; Mathea, Sebastian; Karvonen, Hanna; Malhotra, Ketan; Chatterjee, Deep; Niininen, Wilhelmiina; Perttilä, Robert; Preuss, Franziska; Suresh, Krishna; Stayrook, Steven E; Tsutsui, Yuko; Radhakrishnan, Ravi; Ungureanu, Daniela; Knapp, Stefan; Lemmon, Mark A.
Afiliação
  • Sheetz JB; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA.
  • Mathea S; Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main 60438, Germany; Buchmann Institute for Molecular Life Sciences, Structural Genomics Consortium, Frankfurt am Main 60438, Germany; German Cancer Consortium DKTK Frankfurt/Mainz, Frankfurt 60438, Germany.
  • Karvonen H; Cancer Signaling, Faculty of Medicine and Health Technology and BioMediTech, Tampere University, Tampere 33014, Finland.
  • Malhotra K; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA.
  • Chatterjee D; Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main 60438, Germany; Buchmann Institute for Molecular Life Sciences, Structural Genomics Consortium, Frankfurt am Main 60438, Germany.
  • Niininen W; Cancer Signaling, Faculty of Medicine and Health Technology and BioMediTech, Tampere University, Tampere 33014, Finland.
  • Perttilä R; Cancer Signaling, Faculty of Medicine and Health Technology and BioMediTech, Tampere University, Tampere 33014, Finland.
  • Preuss F; Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main 60438, Germany; Buchmann Institute for Molecular Life Sciences, Structural Genomics Consortium, Frankfurt am Main 60438, Germany.
  • Suresh K; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Stayrook SE; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA.
  • Tsutsui Y; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA.
  • Radhakrishnan R; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Ungureanu D; Cancer Signaling, Faculty of Medicine and Health Technology and BioMediTech, Tampere University, Tampere 33014, Finland; Genome-Scale Biology, Research Programs Unit, University of Helsinki, Helsinki 00014, Finland. Electronic address: daniela.ungureanu@tuni.fi.
  • Knapp S; Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main 60438, Germany; Buchmann Institute for Molecular Life Sciences, Structural Genomics Consortium, Frankfurt am Main 60438, Germany; German Cancer Consortium DKTK Frankfurt/Mainz, Frankfurt 60438, Germany. Elec
  • Lemmon MA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA. Electronic address: mark.lemmon@yale.edu.
Mol Cell ; 79(3): 390-405.e7, 2020 08 06.
Article em En | MEDLINE | ID: mdl-32619402
Despite their apparent lack of catalytic activity, pseudokinases are essential signaling molecules. Here, we describe the structural and dynamic properties of pseudokinase domains from the Wnt-binding receptor tyrosine kinases (PTK7, ROR1, ROR2, and RYK), which play important roles in development. We determined structures of all pseudokinase domains in this family and found that they share a conserved inactive conformation in their activation loop that resembles the autoinhibited insulin receptor kinase (IRK). They also have inaccessible ATP-binding pockets, occluded by aromatic residues that mimic a cofactor-bound state. Structural comparisons revealed significant domain plasticity and alternative interactions that substitute for absent conserved motifs. The pseudokinases also showed dynamic properties that were strikingly similar to those of IRK. Despite the inaccessible ATP site, screening identified ATP-competitive type-II inhibitors for ROR1. Our results set the stage for an emerging therapeutic modality of "conformational disruptors" to inhibit or modulate non-catalytic functions of pseudokinases deregulated in disease.
Assuntos
Moléculas de Adesão Celular/química; Inibidores de Proteínas Quinases/farmacologia; Receptores Proteína Tirosina Quinases/química; Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/química; Sequência de Aminoácidos; Animais; Baculoviridae/genética; Baculoviridae/metabolismo; Sítios de Ligação; Moléculas de Adesão Celular/antagonistas & inibidores; Moléculas de Adesão Celular/genética; Moléculas de Adesão Celular/metabolismo; Linhagem Celular; Clonagem Molecular; Cristalografia por Raios X; Expressão Gênica; Humanos; Camundongos; Modelos Moleculares; Células Precursoras de Linfócitos B/citologia; Células Precursoras de Linfócitos B/metabolismo; Ligação Proteica; Conformação Proteica em alfa-Hélice; Conformação Proteica em Folha beta; Domínios e Motivos de Interação entre Proteínas; Inibidores de Proteínas Quinases/química; Receptores Proteína Tirosina Quinases/antagonistas & inibidores; Receptores Proteína Tirosina Quinases/genética; Receptores Proteína Tirosina Quinases/metabolismo; Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores; Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética; Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo; Receptores da Família Eph/antagonistas & inibidores; Receptores da Família Eph/química; Receptores da Família Eph/genética; Receptores da Família Eph/metabolismo; Proteínas Recombinantes/química; Proteínas Recombinantes/genética; Proteínas Recombinantes/metabolismo; Células Sf9; Bibliotecas de Moléculas Pequenas/química; Bibliotecas de Moléculas Pequenas/farmacologia; Spodoptera; Homologia Estrutural de Proteína; Especificidade por Substrato
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Moléculas de Adesão Celular / Receptores Proteína Tirosina Quinases / Inibidores de Proteínas Quinases / Receptores Órfãos Semelhantes a Receptor Tirosina Quinase Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Moléculas de Adesão Celular / Receptores Proteína Tirosina Quinases / Inibidores de Proteínas Quinases / Receptores Órfãos Semelhantes a Receptor Tirosina Quinase Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article