5JSB

Crystal structure of Mcl1-inhibitor complex

Summary for 5JSB

• Entry DOI: 10.2210/pdb5jsb/pdb
• Related: 4OYD 5JSN
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Mcl-1 inhibitor (3 entities in total)
• Functional Keywords: mcl-1, antimcl1, complex, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 202323.85

Authors

Shen, B.W.,Stoddard, B.L. (deposition date: 2016-05-07, release date: 2016-11-16, Last modification date: 2024-04-03)

Primary citation

Berger, S.,Procko, E.,Margineantu, D.,Lee, E.F.,Shen, B.W.,Zelter, A.,Silva, D.A.,Chawla, K.,Herold, M.J.,Garnier, J.M.,Johnson, R.,MacCoss, M.J.,Lessene, G.,Davis, T.N.,Stayton, P.S.,Stoddard, B.L.,Fairlie, W.D.,Hockenbery, D.M.,Baker, D.
Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer.
Elife, 5:-, 2016

PubMed Abstract: Many cancers overexpress one or more of the six human pro-survival BCL2 family proteins to evade apoptosis. To determine which BCL2 protein or proteins block apoptosis in different cancers, we computationally designed three-helix bundle protein inhibitors specific for each BCL2 pro-survival protein. Following in vitro optimization, each inhibitor binds its target with high picomolar to low nanomolar affinity and at least 300-fold specificity. Expression of the designed inhibitors in human cancer cell lines revealed unique dependencies on BCL2 proteins for survival which could not be inferred from other BCL2 profiling methods. Our results show that designed inhibitors can be generated for each member of a closely-knit protein family to probe the importance of specific protein-protein interactions in complex biological processes.

PubMed: 27805565
DOI: 10.7554/eLife.20352

Experimental method

X-RAY DIFFRACTION (2.74 Å)