Event Abstract Back to Event Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules Natalya Gertsik1, 2, Yue-Ming Li1, 3 and De-Ming Chau4* 1 Memorial Sloan-Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, United States 2 Weill Graduate School of Medical Sciences of Cornell University, Biochemistry and Molecular Biology Program, United States 3 Weill Graduate School of Medical Sciences of Cornell University, Program of Pharmacology, United States 4 Universiti Putra Malaysia, Department of Biomedical Science, Faculty of Medicine & Health Sciences, Malaysia Gamma-secretase is a membrane-bound aspartyl-protease that cleaves many membrane substrates including Amyloid Precursor Protein (APP), Notch, E-cadherin, Her4 and CD44. APP is a particularly notable substrate because of its association with Alzheimer disease. Together, gamma-secretase and beta-secretase cleave APP to produce amyloid beta peptides that aggregate in the brain as cytotoxic beta-amlyoid plaques, which is one of the hallmarks of Alzheimer disease. Many small molecules are being developed to target gamma-secretase as a therapeutic strategy for Alzheimer disease. However, studying the effects of these molecules on the active site conformation of gamma-secretase is challenging due to the complexity of this enzyme. In our study, we have developed new biochemical techniques to probe the active site structure of gamma-secretase. We are able to show that different gamma-secretase inhibitors and modulators, when bind to gamma-secretase, affect the active site structure of gamma-secretase differently. More importantly, we discovered that these small molecules, which were developed to target gamma-secretase, also affect the active site structure of Signal Peptide Peptidase, a similar membrane-bound aspartyl-protease. This discovery has major implication on the development of gamma-secretase inhibitors as therapeutic drugs for Alzheimer disease due to potential off-target effects. Keywords: neurodegeneration, Alzheimer’s disease, therapeutic, molecule, Gamma secretase Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: Poster Presentation Session Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Gertsik N, Li Y and Chau D (2016). Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00137 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. De-Ming Chau, Universiti Putra Malaysia, Department of Biomedical Science, Faculty of Medicine & Health Sciences, Serdang, Selangor, Malaysia, chau.deming@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Natalya Gertsik Yue-Ming Li De-Ming Chau Google Natalya Gertsik Yue-Ming Li De-Ming Chau Google Scholar Natalya Gertsik Yue-Ming Li De-Ming Chau PubMed Natalya Gertsik Yue-Ming Li De-Ming Chau Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.