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TitleDe novo design of transmembrane fluorescence-activating proteins.
Journal, issue, pagesNature, Vol. 640, Issue 8057, Page 249-257, Year 2025
Publish dateFeb 19, 2025
AuthorsJingyi Zhu / Mingfu Liang / Ke Sun / Yu Wei / Ruiying Guo / Lijing Zhang / Junhui Shi / Dan Ma / Qi Hu / Gaoxingyu Huang / Peilong Lu /
PubMed AbstractThe recognition of ligands by transmembrane proteins is essential for the exchange of materials, energy and information across biological membranes. Progress has been made in the de novo design of ...The recognition of ligands by transmembrane proteins is essential for the exchange of materials, energy and information across biological membranes. Progress has been made in the de novo design of transmembrane proteins, as well as in designing water-soluble proteins to bind small molecules, but de novo design of transmembrane proteins that tightly and specifically bind to small molecules remains an outstanding challenge. Here we present the accurate design of ligand-binding transmembrane proteins by integrating deep learning and energy-based methods. We designed pre-organized ligand-binding pockets in high-quality four-helix backbones for a fluorogenic ligand, and generated a transmembrane span using gradient-guided hallucination. The designer transmembrane proteins specifically activated fluorescence of the target fluorophore with mid-nanomolar affinity, exhibiting higher brightness and quantum yield compared to those of enhanced green fluorescent protein. These proteins were highly active in the membrane fraction of live bacterial and eukaryotic cells following expression. The crystal and cryogenic electron microscopy structures of the designer protein-ligand complexes were very close to the structures of the design models. We showed that the interactions between ligands and transmembrane proteins within the membrane can be accurately designed. Our work paves the way for the creation of new functional transmembrane proteins, with a wide range of applications including imaging, ligand sensing and membrane transport.
External linksNature / PubMed:39972138
MethodsEM (single particle) / X-ray diffraction
Resolution2.1 - 2.74 Å
Structure data

60929

9ivk

EMDB-60929, PDB-9ivk:
cryo-EM structure of a tmFAP
Method: EM (single particle) / Resolution: 2.74 Å

PDB-8w6e:
De novo design of HBC599 binder
Method: X-RAY DIFFRACTION / Resolution: 2.1 Å

PDB-8w6f:
Apo structure of HBC binder
Method: X-RAY DIFFRACTION / Resolution: 2.35 Å

Chemicals

ChemComp-KY6:
4-[(Z)-1-cyano-2-{6-[(2-hydroxyethyl)(methyl)amino]-1-benzothiophen-2-yl}ethenyl]benzonitrile

ChemComp-HOH:
WATER

Source
  • artificial sequences (others)
  • homo sapiens (human)
KeywordsDE NOVO PROTEIN / de novo protein design; ligand binding; fluorogenic; fluorescent protein / ligand binding / fluorogenic / fluorescent protein / MEMBRANE PROTEIN/IMMUNE SYSTEM / de novo protein design; transmembrane protein; ligand binding; fluorogenic; membrane; fluorescent protein. / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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