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Structural insights into the role and targeting of EGFRvIII.
Bagchi, Atrish; Stayrook, Steven E; Xenaki, Katerina T; Starbird, Chrystal A; Doulkeridou, Sofia; El Khoulati, Rachid; Roovers, Rob C; Schmitz, Karl R; van Bergen En Henegouwen, Paul M P; Ferguson, Kathryn M.
Afiliación
  • Bagchi A; Graduate Group in Biochemistry and Molecular Biophysics, 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.
  • Xenaki KT; Division of Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, Utrecht 3584CH, the Netherlands.
  • Starbird CA; 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.
  • Doulkeridou S; Division of Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, Utrecht 3584CH, the Netherlands.
  • El Khoulati R; Division of Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, Utrecht 3584CH, the Netherlands.
  • Roovers RC; Division of Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, Utrecht 3584CH, the Netherlands.
  • Schmitz KR; Department of Biological Sciences, University of Delaware, Newark, DE, USA.
  • van Bergen En Henegouwen PMP; Division of Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, Utrecht 3584CH, the Netherlands.
  • Ferguson KM; 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: kathryn.ferguson@yale.edu.
Structure ; 32(9): 1367-1380.e6, 2024 Sep 05.
Article en En | MEDLINE | ID: mdl-38908376
ABSTRACT
The epidermal growth factor receptor (EGFR) is a well-known oncogenic driver in lung and other cancers. In glioblastoma multiforme (GBM), the EGFR deletion variant III (EGFRvIII) is frequently found alongside EGFR amplification. Agents targeting the EGFR axis have shown limited clinical benefits in GBM and the role of EGFRvIII in GBM is poorly understood. To shed light on the role of EGFRvIII and its potential as a therapeutic target, we determined X-ray crystal structures of a monomeric EGFRvIII extracellular region (ECR). The EGFRvIII ECR resembles the unliganded conformation of EGFR, including the orientation of the C-terminal region of domain II. Domain II is mostly disordered, but the ECR structure is compact. We selected a nanobody with preferential binding to EGFRvIII relative to EGFR and structurally defined an epitope on domain IV that is occluded in the unliganded intact EGFR. These findings suggest new avenues for EGFRvIII targeting in GBM.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Unión Proteica / Anticuerpos de Dominio Único / Receptores ErbB Límite: Humans Idioma: En Revista: Structure Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Unión Proteica / Anticuerpos de Dominio Único / Receptores ErbB Límite: Humans Idioma: En Revista: Structure Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos