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Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes
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 biophysica...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887256/ https://www.ncbi.nlm.nih.gov/pubmed/24210759 http://dx.doi.org/10.1016/j.str.2013.09.018 |
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author | Li, Yi Lu, Stephen Hsueh-Jeng Tsai, Ching-Ju Bohm, Christopher Qamar, Seema Dodd, Roger B. Meadows, William Jeon, Amy McLeod, Adam Chen, Fusheng Arimon, Muriel Berezovska, Oksana Hyman, Bradley T. Tomita, Taisuke Iwatsubo, Takeshi Johnson, Christopher M. Farrer, Lindsay A. Schmitt-Ulms, Gerold Fraser, Paul E. St George-Hyslop, Peter H. |
author_facet | Li, Yi Lu, Stephen Hsueh-Jeng Tsai, Ching-Ju Bohm, Christopher Qamar, Seema Dodd, Roger B. Meadows, William Jeon, Amy McLeod, Adam Chen, Fusheng Arimon, Muriel Berezovska, Oksana Hyman, Bradley T. Tomita, Taisuke Iwatsubo, Takeshi Johnson, Christopher M. Farrer, Lindsay A. Schmitt-Ulms, Gerold Fraser, Paul E. St George-Hyslop, Peter H. |
author_sort | Li, Yi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3887256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-38872562014-01-10 Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes Li, Yi Lu, Stephen Hsueh-Jeng Tsai, Ching-Ju Bohm, Christopher Qamar, Seema Dodd, Roger B. Meadows, William Jeon, Amy McLeod, Adam Chen, Fusheng Arimon, Muriel Berezovska, Oksana Hyman, Bradley T. Tomita, Taisuke Iwatsubo, Takeshi Johnson, Christopher M. Farrer, Lindsay A. Schmitt-Ulms, Gerold Fraser, Paul E. St George-Hyslop, Peter H. Structure Article 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. Cell Press 2014-01-07 /pmc/articles/PMC3887256/ /pubmed/24210759 http://dx.doi.org/10.1016/j.str.2013.09.018 Text en © 2014 The Authors https://creativecommons.org/licenses/by/3.0/This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Li, Yi Lu, Stephen Hsueh-Jeng Tsai, Ching-Ju Bohm, Christopher Qamar, Seema Dodd, Roger B. Meadows, William Jeon, Amy McLeod, Adam Chen, Fusheng Arimon, Muriel Berezovska, Oksana Hyman, Bradley T. Tomita, Taisuke Iwatsubo, Takeshi Johnson, Christopher M. Farrer, Lindsay A. Schmitt-Ulms, Gerold Fraser, Paul E. St George-Hyslop, Peter H. Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes |
title | Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes |
title_full | Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes |
title_fullStr | Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes |
title_full_unstemmed | Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes |
title_short | Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes |
title_sort | structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human ps1 complexes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887256/ https://www.ncbi.nlm.nih.gov/pubmed/24210759 http://dx.doi.org/10.1016/j.str.2013.09.018 |
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