Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer
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....
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2016-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/20352 |
| _version_ | 1811202666639917056 |
|---|---|
| author | Stephanie Berger Erik Procko Daciana Margineantu Erinna F Lee Betty W Shen Alex Zelter Daniel-Adriano Silva Kusum Chawla Marco J Herold Jean-Marc Garnier Richard Johnson Michael J MacCoss Guillaume Lessene Trisha N Davis Patrick S Stayton Barry L Stoddard W Douglas Fairlie David M Hockenbery David Baker |
| author_facet | Stephanie Berger Erik Procko Daciana Margineantu Erinna F Lee Betty W Shen Alex Zelter Daniel-Adriano Silva Kusum Chawla Marco J Herold Jean-Marc Garnier Richard Johnson Michael J MacCoss Guillaume Lessene Trisha N Davis Patrick S Stayton Barry L Stoddard W Douglas Fairlie David M Hockenbery David Baker |
| author_sort | Stephanie Berger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:43:36Z |
| format | Article |
| id | doaj.art-da3cabaf1a264379bba52814db23e987 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:43:36Z |
| publishDate | 2016-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-da3cabaf1a264379bba52814db23e9872022-12-22T03:51:16ZengeLife Sciences Publications LtdeLife2050-084X2016-11-01510.7554/eLife.20352Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancerStephanie Berger0https://orcid.org/0000-0002-3738-5907Erik Procko1Daciana Margineantu2Erinna F Lee3Betty W Shen4Alex Zelter5Daniel-Adriano Silva6Kusum Chawla7Marco J Herold8Jean-Marc Garnier9Richard Johnson10Michael J MacCoss11Guillaume Lessene12https://orcid.org/0000-0002-1193-8147Trisha N Davis13https://orcid.org/0000-0003-4797-3152Patrick S Stayton14Barry L Stoddard15W Douglas Fairlie16David M Hockenbery17David Baker18https://orcid.org/0000-0001-7896-6217Department of Bioengineering, University of Washington, Seattle, United StatesDepartment of Biochemistry, University of Washington, Seattle, United States; Department of Biochemistry, University of Illinois, Urbana, United StatesClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesDepartment of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, AustraliaBasic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesDepartment of Biochemistry, University of Washington, Seattle, United StatesDepartment of Biochemistry, University of Washington, Seattle, United States; Institute for Protein Design, University of Washington, Seattle, United StatesClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesThe Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, AustraliaDepartment of Genome Sciences, University of Washington, Seattle, United StatesDepartment of Genome Sciences, University of Washington, Seattle, United StatesThe Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, AustraliaDepartment of Biochemistry, University of Washington, Seattle, United StatesDepartment of Bioengineering, University of Washington, Seattle, United StatesBasic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesDepartment of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, AustraliaClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesDepartment of Biochemistry, University of Washington, Seattle, United States; Institute for Protein Design, University of Washington, Seattle, United States; Howard Hughes Medical Institute, University of Washington, Seattle, United StatesMany 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.https://elifesciences.org/articles/20352computational protein designcancerBcl-2 |
| spellingShingle | Stephanie Berger Erik Procko Daciana Margineantu Erinna F Lee Betty W Shen Alex Zelter Daniel-Adriano Silva Kusum Chawla Marco J Herold Jean-Marc Garnier Richard Johnson Michael J MacCoss Guillaume Lessene Trisha N Davis Patrick S Stayton Barry L Stoddard W Douglas Fairlie David M Hockenbery David Baker Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer eLife computational protein design cancer Bcl-2 |
| title | Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer |
| title_full | Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer |
| title_fullStr | Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer |
| title_full_unstemmed | Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer |
| title_short | Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer |
| title_sort | computationally designed high specificity inhibitors delineate the roles of bcl2 family proteins in cancer |
| topic | computational protein design cancer Bcl-2 |
| url | https://elifesciences.org/articles/20352 |
| work_keys_str_mv | AT stephanieberger computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT erikprocko computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT dacianamargineantu computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT erinnaflee computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT bettywshen computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT alexzelter computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT danieladrianosilva computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT kusumchawla computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT marcojherold computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT jeanmarcgarnier computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT richardjohnson computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT michaeljmaccoss computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT guillaumelessene computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT trishandavis computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT patricksstayton computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT barrylstoddard computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT wdouglasfairlie computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT davidmhockenbery computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer AT davidbaker computationallydesignedhighspecificityinhibitorsdelineatetherolesofbcl2familyproteinsincancer |