Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Streptomycin sulfate synthesis CRTH belongs to a group of no

    2020-08-03

    CRTH2 belongs to a group of non-chemokine chemoattractant GPCRs that are phylogenetically close to each other but recognize very diverse ligands from lipids to peptides to large proteins (Figures S1A and S2A). The structures of CRTH2 reported here, together with the previously reported structures of BLT1 and C5aR, show a large structural divergence of the extracellular region in those receptors, likely accounting for the recognition of diverse ligands by those GPCRs. On the other hand, the structures also reveal a conserved structural feature in these receptors. One residue in TM6, Y6.51, which is conserved as a Y or F in other non-chemokine chemoattractant GPCRs, directly interacts with the ligands of all three receptors (Figure S7). This residue sits on top of a structural motif F6.44XXCW6.48XP6.50 that is highly conserved in rhodopsin-like GPCRs and interacts with W6.48, which has been suggested to function as a toggle switch in the activation of some GPCRs (Smit et al., 2007). We propose that for the group of non-chemokine chemoattractant GPCRs, the three conserved residues, F6.44, W6.48, and Y/F6.51, line up in TM6 to constitute a critical structural motif that mediates the propagation of signal from the extracellular ligand binding pocket to the cytoplasmic region that interacts with intracellular signaling molecules in receptor activation. The two receptors, CRTH2 and BLT1, apparently adopt different mechanisms for lipid recognition, with distinct ligand binding pockets, even though the endogenous ligands for BLT1 and CRTH2, LTB4, and PGD2, respectively, are both eicosanoid lipid mediators with a high chemical similarity (Figure S2A). Some other members of this group of GPCRs, including FPR2/ALX, ChemR23 (CMKLR1), and GPR32, recognize a special group of eicosanoid lipids called specialized pro-resolving lipid mediators (SPMs). SPMs can promote the resolution of inflammation, in Streptomycin sulfate synthesis to the primary pro-inflammatory function of most eicosanoid lipids, including LTB4 and PGD2. Whether the recognition of SPMs by their receptors is similar to the lipid recognition by BLT1 or by CRTH2 needs further investigation. This is important considering the increasing research interests in developing new pro-resolving mediators as a novel therapy for treating inflammatory diseases (Dalli and Serhan, 2018). In addition, one member of this group, FPR2/ALX, can sense both formyl peptides and SPMs. The molecular mechanism for such promiscuous ligand recognition remains elusive. Our structures also provide new insights into CRTH2 drug development. The ligand binding pocket revealed by our structures comprises many aromatic residues and a few polar residues at the distal end. Correspondingly, most CRTH2 antagonists share a similar structural feature characterized by an acetate polar group attached to a central aromatic group to fit the ligand binding pocket (Pettipher and Whittaker, 2012). The different binding poses of the tail groups of CAY10471 and fevipiprant associated with the different conformations of W2837.32 and the N-loop indicate that the open end of the ligand binding pocket, which we propose to be the ligand entry port, exhibits certain structural flexibility. Additional structures of CRTH2 with other antagonists that have distinct tail groups are needed to further investigate the conformational diversity of residues in this region, as it may significantly affect the results of structure-based virtual screening for developing novel CRTH2 antagonists. Furthermore, the unexpected small molecules modeled in this region suggest that the ligand entry port may offer an additional site for designing new synthetic CRTH2 antagonists, which compared to CAY10471 and fevipiprant would engage in additional interactions with the receptor to achieve stronger binding and a longer duration of action.