8U27

Bcl-2-xL complexed with compound 35

Summary for 8U27

• Entry DOI: 10.2210/pdb8u27/pdb
• NMR Information: BMRB: 52100
• Descriptor: Apoptosis regulator Bcl-2, Bcl-2-like protein 1 chimera, propan-2-yl {4-[(5S)-1-(4-bromobenzoyl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl]phenyl}carbamate (2 entities in total)
• Functional Keywords: autophagy, apoptosis, selective inhibition
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 21199.52

Authors

Rizo, J.,Pan, Y.-Z. (deposition date: 2023-09-05, release date: 2023-09-13, Last modification date: 2024-05-15)

Primary citation

Pan, Y.Z.,Liang, Q.,Tomchick, D.R.,De Brabander, J.K.,Rizo, J.
Structural insights for selective disruption of Beclin 1 binding to Bcl-2.
Commun Biol, 6:1080-1080, 2023

PubMed 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.

PubMed: 37875561
DOI: 10.1038/s42003-023-05467-w

Experimental method

SOLUTION NMR