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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: 3kj0, 3kj1, 3kj2

Cited: 62 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.

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Articles - 2pqk mentioned but not cited (25)

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  19. Antibody fragments structurally enable a drug-discovery campaign on the cancer target Mcl-1. Luptak J, Bista M, Fisher D, Flavell L, Gao N, Wickson K, Kazmirski SL, Howard T, Rawlins PB, Hargreaves D. Acta Crystallogr D Struct Biol 75 1003-1014 (2019)
  20. 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)
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  2. Protein binding specificity versus promiscuity. Schreiber G, Keating AE. Curr Opin Struct Biol 21 50-61 (2011)
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  5. 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. 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. 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)
  3. 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)
  4. 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)
  5. 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)
  6. 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)
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  8. 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)
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  12. 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)
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  15. 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)
  16. 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)
  17. 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)
  18. 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)
  19. Heavy lessons in protein allostery. Konermann L. Nat Struct Mol Biol 23 511-512 (2016)
  20. 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)
  21. 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)
  22. 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 eabe1682 (2021)
  23. 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)
  24. 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)
  25. 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 E1308 (2020)
  26. A novel peptide derived from Zingiber cassumunar rhizomes exhibits anticancer activity against the colon adenocarcinoma cells (Caco-2) via the induction of intrinsic apoptosis signaling. Promsut K, Sangtanoo P, Srimongkol P, Saisavoey T, Puthong S, Buakeaw A, Reamtong O, Nutho B, Karnchanatat A. PLoS One 19 e0304701 (2024)
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