Cryo-EM

— The world's leading commercial Cryo-EM center.

  • 01
    One-Stop Solution
  • 02
    Cutting-Edge Instruments
  • 03
    Experienced Teams

Membrane Proteins

GPCRs

  • GLP-1R

    2.8 Å
    37723
    P43220

  • S1PR3

    2.8 Å
    37748
    Q99500

  • AA2AR

    3.1 Å
    P29274

  • CCR8

    2.7 Å
    P51685

The G protein-coupled receptors (GPCRs) superfamily is a class of proteins characterized by a classic seven-transmembrane helix structure, representing the largest family of membrane protein receptors in the human body. To date, over 800 members of the GPCR superfamily have been identified, widely distributed across various tissues and organs. It is estimated that over 30% of marketed drugs target GPCRs. Therefore, research into the functional regulatory mechanisms of GPCRs and related drug development are crucial for treating numerous diseases.

GPCR forms a transient complex with agonist and the G protein bound to guanosine diphosphate (GDP) (GPCR-GGDP), inducing the release of GDP and resulting in a nucleotide-free GPCR-G protein complex (GPCR-Gempty). Guanosine triphosphate (GTP) then binds to the G protein in the GPCR-Gempty state, causing the dissociation of the G protein into Gα and Gβγ subunits. These subunits subsequently activate downstream target proteins to transmit cellular signals 【1-4】 .

Antagonists are molecules that bind to GPCRs without initiating signal transduction. They can competitively block the binding of agonists to the receptor, thereby inhibiting receptor activity. Antagonists are commonly used to treat certain diseases, such as inhibiting abnormally activated receptors.

However, a core challenge in cryo-electron microscopy (Cryo-EM) is that the resolution of 3D reconstruction depends on the accuracy of aligning individual molecular images. The average molecular weight of most GPCRs is less than 40 kDa, with their key structural features embedded within the membrane. In purification systems, these regions typically reside in detergent micelles or lipid nanodiscs. The insertion of the intracellular loop 3 (ICL3) into a fusion protein, BRIL, has enabled the interrogation of antagonist-bound receptors and, particularly, unliganded receptors 【5】 .

References

【1】 Zhang X, Belousoff M J, Zhao P, et al. Differential GLP-1R binding and activation by peptide and non-peptide agonists[J]. Molecular Cell, 2020, 80(3): 485-500. e7.
【2】 Zhao C, Cheng L, Wang W, et al. Structural insights into sphingosine-1-phosphate recognition and ligand selectivity of S1PR3–Gi signaling complexes[J]. Cell research, 2022, 32(2): 218-221.
【3】 Martynowycz M W, Shiriaeva A, Ge X, et al. MicroED structure of the human adenosine receptor determined from a single nanocrystal in LCP[J]. Proceedings of the National Academy of Sciences, 2021, 118(36): e2106041118.
【4】 Jiang S, Lin X, Wu L, et al. Unveiling the structural mechanisms of nonpeptide ligand recognition and activation in human chemokine receptor CCR8[J]. Science Advances, 2024, 10(5): eadj7500.
【5】 Zhang K, Wu H, Hoppe N, et al. Fusion protein strategies for cryo-EM study of G protein-coupled receptors[J]. Nature Communications, 2022, 13(1): 4366.

Single Particle Analysis (SPA)

Cryo-EM Structure Gallery

Single Particle Analysis