title: The influence of adnectin binding on the extracellular domain of epidermal growth factor receptor.
abstract: The precise and unambiguous elucidation and characterization of interactions between a high affinity recognition entity and its cognate protein provides important insights for the design and development of drugs with optimized properties and efficacy. In oncology, one important target protein has been shown to be the epidermal growth factor receptor (EGFR) through the development of therapeutic anticancer antibodies that are selective inhibitors of EGFR activity. More recently, smaller protein derived from the 10th type III domain of human fibronectin termed an adnectin has also been shown to inhibit EGFR in clinical studies. The mechanism of EGFR inhibition by either an adnectin or an antibody results from specific binding of the high affinity protein to the extracellular portion of EGFR (exEGFR) in a manner that prevents phosphorylation of the intracellular kinase domain of the receptor and thereby blocks intracellular signaling. Here, the structural changes induced upon binding were studied by probing the solution conformations of full length exEGFR alone and bound to a cognate adnectin through hydrogen/deuterium exchange mass spectrometry (HDX MS). The effects of binding in solution were identified and compared with the structure of a bound complex determined by X-ray crystallography.ᅟ
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA.
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Iacob
authors.forename: Guodong
authors.initials: G
authors.lastname: Chen
authors.forename: Joomi
authors.initials: J
authors.lastname: Ahn
authors.forename: Stephane
authors.initials: S
authors.lastname: Houel
authors.forename: Hui
authors.initials: H
authors.lastname: Wei
authors.forename: Jingjie
authors.initials: J
authors.lastname: Mo
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
authors.forename: Dianlin
authors.initials: D
authors.lastname: Xie
authors.forename: Zheng
authors.initials: Z
authors.lastname: Lin
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.forename: Michael L
authors.initials: ML
authors.lastname: Doyle
authors.forename: Adrienne A
authors.initials: AA
authors.lastname: Tymiak
authors.forename: John R
authors.initials: JR
authors.lastname: Engen
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D041961:Deuterium Exchange Measurement; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D005353:Fibronectins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D005353:Fibronectins; D066246:ErbB Receptors