title: Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.
abstract: Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors. The complexes are bilobed. The head contains nicastrin ectodomain. The membrane-embedded base has a central channel and a lateral cleft, which may represent the initial substrate docking site. Inhibitor binding induces widespread structural changes, including rotation of the head and closure of the lateral cleft. These changes block substrate access to the catalytic pocket and inhibit the enzyme. Intriguingly, peptide substrate docking has reciprocal effects on the inhibitor binding site. Similar reciprocal shifts may underlie the mechanisms of other inhibitors and of the "lateral gate" through which substrates access to the catalytic site.
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Stephen Hsueh-Jeng
authors.initials: SH
authors.lastname: Lu
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Ching-Ju
authors.initials: CJ
authors.lastname: Tsai
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bohm
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Seema
authors.initials: S
authors.lastname: Qamar
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Dodd
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: William
authors.initials: W
authors.lastname: Meadows
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Jeon
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: McLeod
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Muriel
authors.initials: M
authors.lastname: Arimon
authors.affiliation: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
authors.affiliation: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, and Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, and Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Johnson
authors.affiliation: Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Genetics and Genomics, Biostatistics, and Epidemiology, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada.
authors.forename: Gerold
authors.initials: G
authors.lastname: Schmitt-Ulms
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada. Electronic address: phs22@cam.ac.uk.
authors.forename: Peter H
authors.initials: PH
authors.lastname: St George-Hyslop
mesh_terms: D000494:Allosteric Regulation; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry; D001570:Benzodiazepinones / Q000737:chemistry*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000737:chemistry*; D053764:Presenilin-1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D001570:Benzodiazepinones; D004791:Enzyme Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; C508853:PSEN1 protein, human; D057786:Peptidomimetics; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases