Structural insights for selective disruption of Beclin 1 binding to Bcl-2
Abstract Stimulation of autophagy could provide powerful therapies for multiple diseases, including cancer and neurodegeneration. An attractive drug target for this purpose is Bcl-2, which inhibits autophagy by binding to the Beclin 1 BH3-domain. However, compounds that preclude Beclin 1/Bcl-2 bindi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-10-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05467-w |
| _version_ | 1797557179940601856 |
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| author | Yun-Zu Pan Qiren Liang Diana R. Tomchick Jef K. De Brabander Josep Rizo |
| author_facet | Yun-Zu Pan Qiren Liang Diana R. Tomchick Jef K. De Brabander Josep Rizo |
| author_sort | Yun-Zu Pan |
| collection | DOAJ |
| description | Abstract Stimulation of autophagy could provide powerful therapies for multiple diseases, including cancer and neurodegeneration. An attractive drug target for this purpose is Bcl-2, which inhibits autophagy by binding to the Beclin 1 BH3-domain. However, compounds that preclude Beclin 1/Bcl-2 binding might also induce apoptosis, which is inhibited by binding of Bcl-2 to BH3-domains of pro-apoptosis factors such as Bax. Here we describe the NMR structure of Bcl-2 bound to 35, a compound that we recently found to inhibit Beclin 1/Bcl-2 binding more potently than Bax/Bcl-2 binding. The structure shows that 35 binds at one end of the BH3-binding groove of Bcl-2. Interestingly, much of the 35-binding site is not involved in binding to Bcl-2 inhibitors described previously and mediates binding to Beclin 1 but not Bax. The structure suggests potential avenues to design compounds that disrupt Beclin 1/Bcl-2 binding and stimulate autophagy without inducing apoptosis. |
| first_indexed | 2024-03-10T17:13:41Z |
| format | Article |
| id | doaj.art-f2cdfe0f6d104515bde8bfd9b9a71b55 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:13:41Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-f2cdfe0f6d104515bde8bfd9b9a71b552023-11-20T10:36:16ZengNature PortfolioCommunications Biology2399-36422023-10-016111310.1038/s42003-023-05467-wStructural insights for selective disruption of Beclin 1 binding to Bcl-2Yun-Zu Pan0Qiren Liang1Diana R. Tomchick2Jef K. De Brabander3Josep Rizo4Department of Biophysics, University of Texas Southwestern Medical CenterDepartment of Biochemistry, University of Texas Southwestern Medical CenterDepartment of Biophysics, University of Texas Southwestern Medical CenterDepartment of Biochemistry, University of Texas Southwestern Medical CenterDepartment of Biophysics, University of Texas Southwestern Medical CenterAbstract Stimulation of autophagy could provide powerful therapies for multiple diseases, including cancer and neurodegeneration. An attractive drug target for this purpose is Bcl-2, which inhibits autophagy by binding to the Beclin 1 BH3-domain. However, compounds that preclude Beclin 1/Bcl-2 binding might also induce apoptosis, which is inhibited by binding of Bcl-2 to BH3-domains of pro-apoptosis factors such as Bax. Here we describe the NMR structure of Bcl-2 bound to 35, a compound that we recently found to inhibit Beclin 1/Bcl-2 binding more potently than Bax/Bcl-2 binding. The structure shows that 35 binds at one end of the BH3-binding groove of Bcl-2. Interestingly, much of the 35-binding site is not involved in binding to Bcl-2 inhibitors described previously and mediates binding to Beclin 1 but not Bax. The structure suggests potential avenues to design compounds that disrupt Beclin 1/Bcl-2 binding and stimulate autophagy without inducing apoptosis.https://doi.org/10.1038/s42003-023-05467-w |
| spellingShingle | Yun-Zu Pan Qiren Liang Diana R. Tomchick Jef K. De Brabander Josep Rizo Structural insights for selective disruption of Beclin 1 binding to Bcl-2 Communications Biology |
| title | Structural insights for selective disruption of Beclin 1 binding to Bcl-2 |
| title_full | Structural insights for selective disruption of Beclin 1 binding to Bcl-2 |
| title_fullStr | Structural insights for selective disruption of Beclin 1 binding to Bcl-2 |
| title_full_unstemmed | Structural insights for selective disruption of Beclin 1 binding to Bcl-2 |
| title_short | Structural insights for selective disruption of Beclin 1 binding to Bcl-2 |
| title_sort | structural insights for selective disruption of beclin 1 binding to bcl 2 |
| url | https://doi.org/10.1038/s42003-023-05467-w |
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