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Mcl-1-Bim complexes accommodate surprising point mutations via minor structural changes.

Fire E, Gullá SV, Grant RA, Keating AE
Protein Sci 19 507-19 (2010)
Related entries: 2pqk, 3kj0, 3kj1

Cited: 52 times
EuropePMC logo PMID: 20066663

Abstract

Mcl-1 is an antiapoptotic Bcl-2-family protein that protects cells against death. Structures of Mcl-1, and of other anti-apoptotic Bcl-2 proteins, reveal a surface groove into which the alpha-helical BH3 regions of certain proapoptotic proteins can bind. Despite high overall structural conservation, differences in this groove afford binding specificity that is important for the mechanism of Bcl-2 family function. We report the crystal structure of human Mcl-1 bound to a BH3 peptide derived from human Bim and the structures for three complexes that accommodate large physicochemical changes at conserved Bim sites. The mutations had surprisingly modest effects on complex stability, and the structures show that Mcl-1 can undergo small changes to accommodate the mutant ligands. For example, a shift in a leucine side chain fills a hole left by an isoleucine-to-alanine mutation at the first hydrophobic buried position of Bim BH3. Larger changes are also observed, with shifting of helix alpha3 accommodating an isoleucine-to-tyrosine mutation at this same position. We surveyed the variation in available Mcl-1 and Bcl-x(L) structures and observed moderate flexibility that is likely critical for facilitating interactions of diverse BH3-only proteins with Mcl-1. With the antiapoptotic Bcl-2 family members attracting significant attention as therapeutic targets, these structures contribute to our growing understanding of how specificity is achieved and can help to guide the design of novel inhibitors that target Mcl-1.

Articles - 3kj2 mentioned but not cited (8)

  1. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. Friberg A, Vigil D, Zhao B, Daniels RN, Burke JP, Garcia-Barrantes PM, Camper D, Chauder BA, Lee T, Olejniczak ET, Fesik SW. J Med Chem 56 15-30 (2013)
  2. Mcl-1-Bim complexes accommodate surprising point mutations via minor structural changes. Fire E, Gullá SV, Grant RA, Keating AE. Protein Sci 19 507-519 (2010)
  3. In silico and in vitro elucidation of BH3 binding specificity toward Bcl-2. London N, Gullá S, Keating AE, Schueler-Furman O. Biochemistry 51 5841-5850 (2012)
  4. Locating Herpesvirus Bcl-2 Homologs in the Specificity Landscape of Anti-Apoptotic Bcl-2 Proteins. Foight GW, Keating AE. J Mol Biol 427 2468-2490 (2015)
  5. High-quality NMR structure of human anti-apoptotic protein domain Mcl-1(171-327) for cancer drug design. Liu G, Poppe L, Aoki K, Yamane H, Lewis J, Szyperski T. PLoS One 9 e96521 (2014)
  6. Crystal structure of peptidyl-tRNA hydrolase from mycobacterium smegmatis reveals novel features related to enzyme dynamics. Kumar A, Singh N, Yadav R, Kumar RP, Sharma S, Arora A, Singh TP. Int J Biochem Mol Biol 3 58-69 (2012)
  7. Discovery of novel helix binding sites at protein-protein interfaces. Yang W, Sun X, Zhang C, Lai L. Comput Struct Biotechnol J 17 1396-1403 (2019)
  8. Characterizing the consensus residue specificity and surface of BCL-2 binding to BH3 ligands using the Knob-Socket model. Yi J, Kellner V, Joo H, Chien N, Patel S, Chaban Z, Tsai J. PLoS One 18 e0281463 (2023)


Reviews citing this publication (7)

  1. Mechanisms of action of Bcl-2 family proteins. Shamas-Din A, Kale J, Leber B, Andrews DW. Cold Spring Harb Perspect Biol 5 a008714 (2013)
  2. Protein binding specificity versus promiscuity. Schreiber G, Keating AE. Curr Opin Struct Biol 21 50-61 (2011)
  3. The deadly landscape of pro-apoptotic BCL-2 proteins in the outer mitochondrial membrane. Luna-Vargas MP, Chipuk JE. FEBS J 283 2676-2689 (2016)
  4. Intrinsically disordered proteins in bcl-2 regulated apoptosis. Rautureau GJ, Day CL, Hinds MG. Int J Mol Sci 11 1808-1824 (2010)
  5. Designing specific protein-protein interactions using computation, experimental library screening, or integrated methods. Chen TS, Keating AE. Protein Sci 21 949-963 (2012)
  6. Progress in targeting the BCL-2 family of proteins. Garner TP, Lopez A, Reyna DE, Spitz AZ, Gavathiotis E. Curr Opin Chem Biol 39 133-142 (2017)
  7. Structural Details of BH3 Motifs and BH3-Mediated Interactions: an Updated Perspective. Sora V, Papaleo E. Front Mol Biosci 9 864874 (2022)

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  1. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. LaBelle JL, Katz SG, Bird GH, Gavathiotis E, Stewart ML, Lawrence C, Fisher JK, Godes M, Pitter K, Kung AL, Walensky LD. J Clin Invest 122 2018-2031 (2012)
  2. A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells. Procko E, Berguig GY, Shen BW, Song Y, Frayo S, Convertine AJ, Margineantu D, Booth G, Correia BE, Cheng Y, Schief WR, Hockenbery DM, Press OW, Stoddard BL, Stayton PS, Baker D. Cell 157 1644-1656 (2014)
  3. Determinants of BH3 binding specificity for Mcl-1 versus Bcl-xL. Dutta S, Gullá S, Chen TS, Fire E, Grant RA, Keating AE. J Mol Biol 398 747-762 (2010)
  4. Letter Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells. Foight GW, Ryan JA, Gullá SV, Letai A, Keating AE. ACS Chem Biol 9 1962-1968 (2014)
  5. Structural basis of Bcl-xL recognition by a BH3-mimetic α/β-peptide generated by sequence-based design. Lee EF, Smith BJ, Horne WS, Mayer KN, Evangelista M, Colman PM, Gellman SH, Fairlie WD. Chembiochem 12 2025-2032 (2011)
  6. From DARPins to LoopDARPins: novel LoopDARPin design allows the selection of low picomolar binders in a single round of ribosome display. Schilling J, Schöppe J, Plückthun A. J Mol Biol 426 691-721 (2014)
  7. Predictive Bcl-2 family binding models rooted in experiment or structure. DeBartolo J, Dutta S, Reich L, Keating AE. J Mol Biol 422 124-144 (2012)
  8. Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein. Petros AM, Swann SL, Song D, Swinger K, Park C, Zhang H, Wendt MD, Kunzer AR, Souers AJ, Sun C. Bioorg Med Chem Lett 24 1484-1488 (2014)
  9. Mcl-1 Phosphorylation without Degradation Mediates Sensitivity to HDAC Inhibitors by Liberating BH3-Only Proteins. Tong J, Zheng X, Tan X, Fletcher R, Nikolovska-Coleska Z, Yu J, Zhang L. Cancer Res 78 4704-4715 (2018)
  10. Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells. Rezaei Araghi R, Bird GH, Ryan JA, Jenson JM, Godes M, Pritz JR, Grant RA, Letai A, Walensky LD, Keating AE. Proc Natl Acad Sci U S A 115 E886-E895 (2018)
  11. Peptide ligands for pro-survival protein Bfl-1 from computationally guided library screening. Dutta S, Chen TS, Keating AE. ACS Chem Biol 8 778-788 (2013)
  12. Analysis of Flexibility and Hotspots in Bcl-xL and Mcl-1 Proteins for the Design of Selective Small-Molecule Inhibitors. Yang CY, Wang S. ACS Med Chem Lett 3 308-312 (2012)
  13. Genome-wide prediction and validation of peptides that bind human prosurvival Bcl-2 proteins. DeBartolo J, Taipale M, Keating AE. PLoS Comput Biol 10 e1003693 (2014)
  14. Bh3 induced conformational changes in Bcl-Xl revealed by crystal structure and comparative analysis. Rajan S, Choi M, Baek K, Yoon HS. Proteins 83 1262-1272 (2015)
  15. Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1. Jenson JM, Ryan JA, Grant RA, Letai A, Keating AE. Elife 6 (2017)
  16. Heterodimerization of BAK and MCL-1 activated by detergent micelles. Liu Q, Gehring K. J Biol Chem 285 41202-41210 (2010)
  17. Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors. Li R, Cheng C, Balasis ME, Liu Y, Garner TP, Daniel KG, Li J, Qin Y, Gavathiotis E, Sebti SM. Eur J Med Chem 90 315-331 (2015)
  18. Molecular dynamics study of small molecule inhibitors of the Bcl-2 family. Acoca S, Cui Q, Shore GC, Purisima EO. Proteins 79 2624-2636 (2011)
  19. DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites. Gowthaman R, Miller SA, Rogers S, Khowsathit J, Lan L, Bai N, Johnson DK, Liu C, Xu L, Anbanandam A, Aubé J, Roy A, Karanicolas J. J Med Chem 59 4152-4170 (2016)
  20. Molecular dynamics study of segment peptides of Bax, Bim, and Mcl-1 BH3 domain of the apoptosis-regulating proteins bound to the anti-apoptotic Mcl-1 protein. Zhao RN, Fan S, Han JG, Liu G. J Biomol Struct Dyn 33 1067-1081 (2015)
  21. Tertiary Structural Motif Sequence Statistics Enable Facile Prediction and Design of Peptides that Bind Anti-apoptotic Bfl-1 and Mcl-1. Frappier V, Jenson JM, Zhou J, Grigoryan G, Keating AE. Structure 27 606-617.e5 (2019)
  22. Deciphering the crucial residues involved in heterodimerization of Bak peptide and anti-apoptotic proteins for apoptosis. Marimuthu P, Singaravelu K. J Biomol Struct Dyn 36 1637-1648 (2018)
  23. Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures. Rosas-Trigueros JL, Correa-Basurto J, Benítez-Cardoza CG, Zamorano-Carrillo A. Protein Sci 20 2035-2046 (2011)
  24. A structural investigation of NRZ mediated apoptosis regulation in zebrafish. Suraweera CD, Caria S, Järvå M, Hinds MG, Kvansakul M. Cell Death Dis 9 967 (2018)
  25. Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of BCL-W. Schilling J, Schöppe J, Sauer E, Plückthun A. J Mol Biol 426 2346-2362 (2014)
  26. Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein Bim. Cheng C, Liu Y, Balasis ME, Garner TP, Li J, Simmons NL, Berndt N, Song H, Pan L, Qin Y, Nicolaou KC, Gavathiotis E, Sebti SM, Li R. Mar Drugs 12 4311-4325 (2014)
  27. Conversion of cell-survival activity of Akt into apoptotic death of cancer cells by two mutations on the BIM BH3 domain. Kim JS, Ku B, Woo TG, Oh AY, Jung YS, Soh YM, Yeom JH, Lee K, Park BJ, Oh BH, Ha NC. Cell Death Dis 6 e1804 (2015)
  28. Structure-Function Analysis of the Mcl-1 Protein Identifies a Novel Senescence-regulating Domain. Demelash A, Pfannenstiel LW, Tannenbaum CS, Li X, Kalady MF, DeVecchio J, Gastman BR. J Biol Chem 290 21962-21975 (2015)
  29. Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1. Murray JB, Davidson J, Chen I, Davis B, Dokurno P, Graham CJ, Harris R, Jordan A, Matassova N, Pedder C, Ray S, Roughley SD, Smith J, Walmsley C, Wang Y, Whitehead N, Williamson DS, Casara P, Le Diguarher T, Hickman J, Stark J, Kotschy A, Geneste O, Hubbard RE. ACS Omega 4 8892-8906 (2019)
  30. Heavy lessons in protein allostery. Konermann L. Nat Struct Mol Biol 23 511-512 (2016)
  31. Prediction of Hot Spots at Myeloid Cell Leukemia-1-Inhibitor Interface Using Energy Estimation and Alanine Scanning Mutagenesis. Marimuthu P, Singaravelu K. Biochemistry 57 1249-1261 (2018)
  32. Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting. Pannecoucke E, Van Trimpont M, Desmet J, Pieters T, Reunes L, Demoen L, Vuylsteke M, Loverix S, Vandenbroucke K, Alard P, Henderikx P, Deroo S, Baatz F, Lorent E, Thiolloy S, Somers K, McGrath Y, Van Vlierberghe P, Lasters I, Savvides SN. Sci Adv 7 (2021)
  33. Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1. Hargreaves D, Carbajo RJ, Bodnarchuk MS, Embrey K, Rawlins PB, Packer M, Degorce SL, Hird AW, Johannes JW, Chiarparin E, Schade M. Proc Natl Acad Sci U S A 120 e2221967120 (2023)
  34. Designing BH3-Mimetic Peptide Inhibitors for the Viral Bcl-2 Homologues A179L and BHRF1: Importance of Long-Range Electrostatic Interactions. Reddy CN, Sankararamakrishnan R. ACS Omega 6 26976-26989 (2021)
  35. Phylogenetic analysis of the MCL1 BH3 binding groove and rBH3 sequence motifs in the p53 and INK4 protein families. McGriff A, Placzek WJ. PLoS One 18 e0277726 (2023)
  36. Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins. Wang H, Guo M, Wei H, Chen Y. Comput Struct Biotechnol J 21 3760-3767 (2023)
  37. Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain. Ramanathan A, Parvatikar A, Chennubhotla SC, Mei Y, Sinha SC. Biomolecules 10 (2020)


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