2. Academic Validation
  3. Structural insights for selective disruption of Beclin 1 binding to Bcl-2

Structural insights for selective disruption of Beclin 1 binding to Bcl-2

  • Commun Biol. 2023 Oct 24;6(1):1080. doi: 10.1038/s42003-023-05467-w.
Yun-Zu Pan 1 2 3,  Qiren Liang 2,  Diana R Tomchick 1,  Jef K De Brabander 2,  Josep Rizo 4 5 6
Affiliations

Affiliations

  • 1 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 3 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 4 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Jose.Rizo-Rey@UTSouthwestern.edu.
  • 5 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Jose.Rizo-Rey@UTSouthwestern.edu.
  • 6 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Jose.Rizo-Rey@UTSouthwestern.edu.
PMID: 37875561 DOI: 10.1038/s42003-023-05467-w
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.

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