GPCR Allosteric Modulator Discovery

  • Yiran Wu
  • Jiahui Tong
  • Kang Ding
  • Qingtong Zhou
  • Suwen ZhaoEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1163)


G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology; about one-third of all marketed drugs target members of this family. GPCR allosteric ligands hold the promise of improved subtype selectivity, spatiotemporal sensitivity, and possible biased property over typical orthosteric ligands. However, only a small number of GPCR allosteric ligands have been approved as drugs or in clinical trials since the discovery process is very challenging. The rapid development of GPCR structural biology leads to the discovery of several allosteric sites and sheds light on understanding the mechanism of GPCR allosteric ligands, which is critical for discovering novel therapeutics. This book chapter summarized different GPCR allosteric modulating mechanisms and discussed validated mechanisms based on allosteric modulator-GPCR complex structures.


GPCR allosteric modulator drug discovery membrane protein structures 



Transmembrane domains (TMD)

the core domain that is common to all GPCRs, consisted by seven-transmembrane helices (TM1–7) that are linked by three extracellular loops (ECL1–3) and three intracellular loops (ICL1–3).


a molecule that binds to and activates a receptor to increase the receptor signaling over basal levels.


a molecule that binds to a receptor and inhibits agonist signaling.

Positive allosteric modulator (PAM)

an allosteric ligand that potentiates an agonist-mediated receptor response is referred to as a positive allosteric modulator.

Negative allosteric modulator (NAM)

an allosteric ligand that attenuates an agonist-mediated receptor response is referred as a negative allosteric modulator.

Neutral allosteric ligand (NAL)

an allosteric ligand that does not affect receptor or orthosteric ligand activity is referred as a neutral allosteric ligand.


an allosteric ligand that is capable of directly activating the receptor from an allosteric site even in the absence of an orthosteric agonist is referred as an ago-PAM.

Bitopic ligand

a hybrid molecule that occupies both orthosteric and allosteric sites to mediate a novel pharmacology.

GPCR generic numbering systems

sequence-based generic GPCR residue numbering systems exist for class A (Ballesteros-Weinstein numbering) [2], class B (Wootten numbering) [20], class C (Pin numbering) [29], and class F (Wang numbering) [61]. A numbering is two numbers separated by a dot. The first number denotes the transmembrane helix (1–7). For the second number, the most conserved position in the helix is assigned as 50. That is, the most conserved residue in a helix x is denoted x 50, while all other residues on the same helix are numbered relative to it. For example, 2.50 denotes the most conserved residue in transmembrane helix 2, while one position after it is 2.51.

Orthosteric binding site

where endogenous ligands bind. For GPCR there are different orthosteric binding site in different classes. In class A and B, the orthosteric site locates among the transmembrane helices close to the extracellular end. In class C and D, the orthosteric site locates in extracellular domain.

Allosteric binding site

sites for ligand binding to a receptor that are remote from the orthosteric binding site.


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Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Yiran Wu
    • 1
  • Jiahui Tong
    • 1
    • 2
  • Kang Ding
    • 1
  • Qingtong Zhou
    • 1
  • Suwen Zhao
    • 1
    • 2
    Email author
  1. 1.iHuman InstituteShanghaiTech UniversityShanghaiChina
  2. 2.School of Life Science and TechnologyShanghaiTech UniversityShanghaiChina

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