Pengju Nie1, Abhishek Vartak2, Yue-Ming Li3. 1. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Pharmacology program, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA. 2. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 3. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Pharmacology program, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA. Electronic address: liy2@mskcc.org.
Abstract
Over two decades, γ-secretase has been the target for extensive therapeutic development due to its pivotal role in pathogenesis of Alzheimer's disease and cancer. However, it has proven to be a challenging task owing to its large set of substrates and our limited understanding of the enzyme's structural and mechanistic features. The scientific community is taking bigger strides towards solving this puzzle with recent advancement in techniques like cryogenic electron microscopy (cryo-EM) and photo-affinity labelling (PAL). This review highlights the significance of the PAL technique with multiple examples of photo-probes developed from γ-secretase inhibitors and modulators. The binding of these probes into active and/or allosteric sites of the enzyme has provided crucial information on the γ-secretase complex and improved our mechanistic understanding of this protease. Combining the knowledge of function and regulation of γ-secretase will be a decisive factor in developing novel γ-secretase modulators and biological therapeutics.
Over two decclass="Disease">ades, γ-secretase has been the target for extensive therapeutic development due to its pivotal role in pathogenesis of n class="Disease">Alzheimer's disease and cancer. However, it has proven to be a challenging task owing to its large set of substrates and our limited understanding of the enzyme's structural and mechanistic features. The scientific community is taking bigger strides towards solving this puzzle with recent advancement in techniques like cryogenic electron microscopy (cryo-EM) and photo-affinity labelling (PAL). This review highlights the significance of the PAL technique with multiple examples of photo-probes developed from γ-secretase inhibitors and modulators. The binding of these probes into active and/or allosteric sites of the enzyme has provided crucial information on the γ-secretase complex and improved our mechanistic understanding of this protease. Combining the knowledge of function and regulation of γ-secretase will be a decisive factor in developing novel γ-secretase modulators and biological therapeutics.
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