Structural insights for selective disruption of Beclin 1 binding to Bcl-2.
Structural insights for selective disruption of Beclin 1 binding to Bcl-2.
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DOI：
10.1038/s42003-023-05467-w
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发表时间：
2023-10-24
影响因子：
5.9
通讯作者：
Rizo, Josep
中科院分区：
文献类型：
--
作者：
Pan, Yun-Zu;Liang, Qiren;Tomchick, Diana R.;De Brabander, Jef K.;Rizo, Josep
刺激自噬可以为多种疾病提供强有力的治疗方法，包括癌症和神经变性。一个有吸引力的药物靶点是Bcl-2，它通过结合Beclin 1 bh3结构域来抑制自噬。然而，阻止Beclin 1/Bcl-2结合的化合物也可能诱导细胞凋亡，Bcl-2与Bax等促凋亡因子的bh3结构域结合可抑制细胞凋亡。在这里，我们描述了Bcl-2结合到35的核磁共振结构，这是一种我们最近发现的比Bax/Bcl-2结合更有效地抑制Beclin 1/Bcl-2结合的化合物。结构表明，35结合在Bcl-2的bh3结合槽的一端。有趣的是，35结合位点的大部分不参与先前描述的Bcl-2抑制剂的结合，并且介导与Beclin 1的结合，而不是与Bax的结合。该结构提示了设计破坏Beclin 1/Bcl-2结合并刺激自噬而不诱导细胞凋亡的化合物的潜在途径。Bcl-2与最近发现的抑制剂结合的核磁共振结构揭示了一个结合位点，可能提供了选择性破坏Bcl-2与Beclin 1结合的可能性。
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. The NMR structure of Bcl-2 bound to a recently discovered inhibitor reveals a binding site that may provide the possibility of selectively disrupting binding of Bcl-2 to Beclin 1.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
4
作者：
Chiang WC;Wei Y;Kuo YC;Wei S;Zhou A;Zou Z;Yehl J;Ranaghan MJ;Skepner A;Bittker JA;Perez JR;Posner BA;Levine B
通讯作者：
Levine B
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
DOI：
10.1073/pnas.041619798
发表时间：
2001-03-13
影响因子：
11.1
作者：
Petros, AM;Medek, A;Fesik, SW
通讯作者：
Fesik, SW
DOI：
10.15252/embj.2021108863
发表时间：
2021-10-01
期刊：
The EMBO journal
影响因子：
--
作者：
Klionsky DJ;Petroni G;Amaravadi RK;Baehrecke EH;Ballabio A;Boya P;Bravo-San Pedro JM;Cadwell K;Cecconi F;Choi AMK;Choi ME;Chu CT;Codogno P;Colombo MI;Cuervo AM;Deretic V;Dikic I;Elazar Z;Eskelinen EL;Fimia GM;Gewirtz DA;Green DR;Hansen M;Jäättelä M;Johansen T;Juhász G;Karantza V;Kraft C;Kroemer G;Ktistakis NT;Kumar S;Lopez-Otin C;Macleod KF;Madeo F;Martinez J;Meléndez A;Mizushima N;Münz C;Penninger JM;Perera RM;Piacentini M;Reggiori F;Rubinsztein DC;Ryan KM;Sadoshima J;Santambrogio L;Scorrano L;Simon HU;Simon AK;Simonsen A;Stolz A;Tavernarakis N;Tooze SA;Yoshimori T;Yuan J;Yue Z;Zhong Q;Galluzzi L;Pietrocola F
通讯作者：
Pietrocola F