8t5e

De novo design of high-affinity protein binders to bioactive helical peptides

spinqualitylabelsall models 8t5e, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8t5e is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Publication Abstract from PubMed Many peptide hormones form an alpha-helix on binding their receptors(1-4), and sensitive methods for their detection 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 by either refining designs generated with other methods, or completely de novo starting from random noise distributions without any subsequent experimental optimization. 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 optimize by partial diffusion both natural and designed proteins, should be broadly useful. De novo design of high-affinity binders of bioactive helical peptides.,Vazquez Torres S, 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. 2024 Feb;626(7998):435-442. doi: 10.1038/s41586-023-06953-1. Epub 2023 , Dec 18. PMID:38109936 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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