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De novo design of GPCR exoframe modulators

  • Lorente, J. S. et al. GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 24, 458–479 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rasmussen, S. G. F. et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477, 549–555 (2011).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kang, Y. et al. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523, 561–567 (2015).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Y. et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546, 248–253 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liang, Y.-L. et al. Phase-plate cryo-EM structure of a class B GPCR–G-protein complex. Nature 546, 118–123 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, K. et al. Tail engagement of arrestin at the glucagon receptor. Nature 620, 904–910 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shen, C. et al. Structural basis of GABAB receptor–Gi protein coupling. Nature 594, 594–598 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mao, C. et al. Cryo-EM structures of inactive and active GABAB receptor. Cell Res. 30, 564–573 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wen, T. et al. Molecular basis of β-arrestin coupling to the metabotropic glutamate receptor mGlu3. Nat. Chem. Biol. 21, 1262–1269 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schiöth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thompson, M. D. et al. G protein-coupled receptor (GPCR) gene variants and human genetic disease. Crit. Rev. Clin. Lab. Sci. 61, 317–346 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Reid, K. M. et al. Loss-of-function variants in DRD1 in infantile parkinsonism-dystonia. Cells 12, 1046 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, W., Guo, D.-Y. & Tao, Y.-X. Therapeutic strategies for diseases caused by loss-of-function mutations in G protein-coupled receptors. Prog. Mol. Biol. Transl. Sci. 161, 181–210 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gaylinn, B. D. et al. The mutant growth hormone-releasing hormone (GHRH) receptor of the little mouse does not bind GHRH. Endocrinology 140, 5066–5074 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • He, J. et al. ASD2023: towards the integrating landscapes of allosteric knowledgebase. Nucleic Acids Res. 52, D376–D383 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Koole, C. et al. Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation. Mol. Pharmacol. 80, 486–497 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leach, K. et al. Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium-sensing receptor by positive and negative allosteric modulators. Endocrinology 154, 1105–1116 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cong, Z. et al. Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. Nat. Commun. 12, 3763 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kumar, K. K. et al. Negative allosteric modulation of the glucagon receptor by RAMP2. Cell 186, 1465–1477 (2023).

    Article 
    PubMed Central 

    Google Scholar
     

  • Chen, H., Qin, Y., Chou, M., Cyster, J. G. & Li, X. Transmembrane protein CD69 acts as an S1PR1 agonist. eLife 12, e88204 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luo, P. et al. Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1. Cell Res. 33, 46–54 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liang, Y.-L. et al. Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature 561, 492–497 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cao, J. et al. A structural basis for amylin receptor phenotype. Science 375, 1371 (2022).

    Article 

    Google Scholar
     

  • Liang, Y.-L. et al. Structure and dynamics of adrenomedullin receptors AM1 and AM2 reveal key mechanisms in the control of receptor phenotype by receptor activity-modifying proteins. ACS Pharmacol. Transl. Sci. 3, 263–284 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, J. et al. Predicting protein-protein interactions in the human proteome. Science 390, 353 (2025).

    Article 

    Google Scholar
     

  • Balbi, P. E. M. et al. Mapping targetable sites on the human surfaceome for the design of novel binders. Preprint at bioRxiv https://doi.org/10.1101/2024.12.16.628626 (2024).

  • Yin, H. et al. Computational design of peptides that target transmembrane helices. Science 315, 1817–1822 (2007).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Mravic, M. et al. De novo designed transmembrane peptides activating the α5β1 integrin. Protein Eng. Des. Sel. 31, 181–190 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mravic, M. et al. De novo-designed transmembrane proteins bind and regulate a cytokine receptor. Nat. Chem. Biol. 20, 751–760 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bennett, N. R. et al. Improving de novo protein binder design with deep learning. Nat. Commun. 14, 2625 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frank, C. et al. Scalable protein design using optimization in a relaxed sequence space. Science 386, 439–445 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pacesa, M. et al. One-shot design of functional protein binders with BindCraft. Nature 646, 483–492 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, B. et al. Designed endocytosis-inducing proteins degrade targets and amplify signals. Nature 638, 796–804 (2024).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Glögl, M. et al. Target-conditioned diffusion generates potent TNFR superfamily antagonists and agonists. Science 386, 1154–1161 (2024).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duart, G. et al. Computational design of BclxL inhibitors that target transmembrane domain interactions. Proc. Natl Acad. Sci. USA 120, e2219648120 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anishchenko, I. et al. De novo protein design by deep network hallucination. Nature 600, 547–552 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dauparas, J. et al. Robust deep learning–based protein sequence design using ProteinMPNN. Science 378, 49–56 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kortemme, T. De novo protein design—From new structures to programmable functions. Cell 187, 526–544 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Evans, R. et al. Protein complex prediction with AlphaFold-Multimer. Preprint at bioRxiv https://doi.org/10.1101/2021.10.04.463034 (2021).

  • Goverde, C. A. et al. Computational design of soluble and functional membrane protein analogues. Nature 631, 449–458 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roney, J. P. & Ovchinnikov, S. State-of-the-art estimation of protein model accuracy using AlphaFold. Phys. Rev. Lett. 129, 238101 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yim, J. et al. SE(3) diffusion model with application to protein backbone generation. In Proc. 40th International Conference on Machine Learning 40001–40039 (JMLR.org, 2023).

  • Watson, J. L. et al. De novo design of protein structure and function with RFdiffusion. Nature 620, 1089–1100 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sahoo, P. et al. A systematic survey of prompt engineering in large language models: techniques and applications. Preprint at https://doi.org/10.48550/arXiv.2402.07927 (2024).

  • Heo, L. & Feig, M. Multi-state modeling of G-protein coupled receptors at experimental accuracy. Proteins 90, 1873–1885 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chun, E. et al. Fusion partner toolchest for the stabilization and crystallization of G protein-coupled receptors. Structure 20, 967–976 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, K., Wu, H., Hoppe, N., Manglik, A. & Cheng, Y. Fusion protein strategies for cryo-EM study of G protein-coupled receptors. Nat. Commun. 13, 4366 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schöneberg, T. & Liebscher, I. Mutations in G protein–coupled receptors: mechanisms, pathophysiology and potential therapeutic approaches. Pharmacol. Rev. 73, 89–119 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Kooistra, A. J. et al. GPCRdb in 2021: integrating GPCR sequence, structure and function. Nucleic Acids Res. 49, D335–D343 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, H. et al. Structural insights into ligand recognition and activation of the melanocortin-4 receptor. Cell Res. 31, 1163–1175 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gray, D. L. et al. Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor. Nat. Commun. 9, 674 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, C. et al. Pharmacological characterization of dopamine receptor DRD1 variants and exploration of their allosteric activation. Biochemistry 64, 2200–2211 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schweke, H. et al. An atlas of protein homo-oligomerization across domains of life. Cell 187, 999–1010 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tunyasuvunakool, K. et al. Highly accurate protein structure prediction for the human proteome. Nature 596, 590–596 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pettersen, E. F. et al. UCSF ChimeraX: Structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mirdita, M. et al. ColabFold: making protein folding accessible to all. Nat. Methods 19, 679–682 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhuang, Y. et al. Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor. Cell Res. 31, 593–596 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Crooks, G. E., Hon, G., Chandonia, J.-M. & Brenner, S. E. WebLogo: a sequence logo generator. Genome Res. 14, 1188–1190 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hunter, J. D. Matplotlib: a 2D graphics environment. Comput. Sci. Eng. 9, 90–95 (2007).

    Article 

    Google Scholar
     

  • Zhuang, Y. et al. Structural insights into the human D1 and D2 dopamine receptor signaling complexes. Cell 184, 931–942 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zivanov, J. et al. A Bayesian approach to single-particle electron cryo-tomography in RELION-4.0. eLife 11, e83724 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Punjani, A., Zhang, H. & Fleet, D. J. Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction. Nat. Methods 17, 1214–1221 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Teng, X. et al. Structural insights into G protein activation by D1 dopamine receptor. Sci. Adv. 8, eabo4158 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Moriarty, N. W., Grosse-Kunstleve, R. W. & Adams, P. D. Electronic ligand builder and optimization workbench (eLBOW): a tool for ligand coordinate and restraint generation. Acta Crystallogr. D 65, 1074–1080 (2009).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leaver-Fay, A. et al. Rosetta3: an object-oriented software suite for the simulation and design of macromolecules. Methods Enzymol. 487, 545–574 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D. 66, 486–501 (2010).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Afonine, P. V. et al. Real-space refinement in Phenix for cryo-EM and crystallography. Acta Crystallogr. D 74, 531–544 (2018).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Afonine, P. V. et al. New tools for the analysis and validation of cryo-EM maps and atomic models. Acta Crystallogr. D 74, 814–840 (2018).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • He, Y., Jin, W.-Q., Shen, Q.-X., Chen, X.-J. & Jin, G.-Z. Expression of dopamine D1 receptor in Sf9 insect cells and agonism of l-12-chloroscoulerine on recombinant D1 receptor. Acta Pharmacol. Sin. 24, 225–229 (2003).

    CAS 
    PubMed 

    Google Scholar
     

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