| Structural highlights
Function
B2L11_HUMAN Induces apoptosis and anoikis. Isoform BimL is more potent than isoform BimEL. Isoform Bim-alpha1, isoform Bim-alpha2 and isoform Bim-alpha3 induce apoptosis, although less potent than isoform BimEL, isoform BimL and isoform BimS. Isoform Bim-gamma induces apoptosis. Isoform Bim-alpha3 induces apoptosis possibly through a caspase-mediated pathway. Isoform BimAC and isoform BimABC lack the ability to induce apoptosis.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Many peptide hormones form an alpha-helix upon binding their receptors(1-4), and sensitive detection methods for them could contribute to better clinical management of disease(5). De novo protein design can now generate binders with high affinity and specificity to structured proteins(6,7). However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here, we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion(8) to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar affinity binders can be generated to helical peptide targets both by refining designs generated with other methods, or completely de novo starting from random noise distributions. To our knowledge these are the highest affinity designed binding proteins against any protein or small molecule target generated directly by computation without any experimental optimisation. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimise by partial diffusion both natural and designed proteins, should be broadly useful.
De novo design of high-affinity binders of bioactive helical peptides.,Torres SV, Leung PJY, Venkatesh P, Lutz ID, Hink F, Huynh HH, Becker J, Yeh AH, Juergens D, Bennett NR, Hoofnagle AN, Huang E, MacCoss MJ, Exposit M, Lee GR, Bera AK, Kang A, De La Cruz J, Levine PM, Li X, Lamb M, Gerben SR, Murray A, Heine P, Korkmaz EN, Nivala J, Stewart L, Watson JL, Rogers JM, Baker D Nature. 2023 Dec 18. doi: 10.1038/s41586-023-06953-1. PMID:38109936[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 1998 Jan 15;17(2):384-95. PMID:9430630 doi:http://dx.doi.org/10.1093/emboj/17.2.384
- ↑ U M, Miyashita T, Shikama Y, Tadokoro K, Yamada M. Molecular cloning and characterization of six novel isoforms of human Bim, a member of the proapoptotic Bcl-2 family. FEBS Lett. 2001 Nov 30;509(1):135-41. PMID:11734221
- ↑ Liu JW, Chandra D, Tang SH, Chopra D, Tang DG. Identification and characterization of Bimgamma, a novel proapoptotic BH3-only splice variant of Bim. Cancer Res. 2002 May 15;62(10):2976-81. PMID:12019181
- ↑ Marani M, Tenev T, Hancock D, Downward J, Lemoine NR. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol. 2002 Jun;22(11):3577-89. PMID:11997495
- ↑ Chen JZ, Ji CN, Gu SH, Li JX, Zhao EP, Huang Y, Huang L, Ying K, Xie Y, Mao YM. Over-expression of Bim alpha3, a novel isoform of human Bim, result in cell apoptosis. Int J Biochem Cell Biol. 2004 Aug;36(8):1554-61. PMID:15147734 doi:http://dx.doi.org/10.1016/j.biocel.2003.12.015
- ↑ Fukazawa H, Noguchi K, Masumi A, Murakami Y, Uehara Y. BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors. Mol Cancer Ther. 2004 Oct;3(10):1281-8. PMID:15486195
- ↑ Torres SV, Leung PJY, Venkatesh P, Lutz ID, Hink F, Huynh HH, Becker J, Yeh AH, Juergens D, Bennett NR, Hoofnagle AN, Huang E, MacCoss MJ, Expòsit M, Lee GR, Bera AK, Kang A, De La Cruz J, Levine PM, Li X, Lamb M, Gerben SR, Murray A, Heine P, Korkmaz EN, Nivala J, Stewart L, Watson JL, Rogers JM, Baker D. De novo design of high-affinity binders of bioactive helical peptides. Nature. 2023 Dec 18. PMID:38109936 doi:10.1038/s41586-023-06953-1
|
