The family of formyl peptide receptors (FPR) are G-protein coupled receptors (GPCRs) that seem to be important in defence against bacterial infections and function as chemoattractant receptors in innate immune responses.1 The three FPRs (FPR1-3) belong to the family of chemoattractant GPCRs such as the complement component receptor C5a (C5aR) or the chemokine IL-8 Receptor (CXCR1/2). N-terminal formylated bacterial signal peptides with variable sequence and length are natural FPR agonists and activate human FPR1 and FPR2 at low nanomolar concentrations. So, these signal peptides function as potent activators of the innate immune system and trigger a range of classical innate defence mechanisms. FPR3 shows a high sequence similarity to FPR2 but displays a narrower spectrum of possible signal peptide variations. The recent availability of the crystal structure2 and the Cryo EM structure3 of FPR2 in complex with the potent peptide agonist WKYMVm-NH2 now allows a more detailed analysis of ligand binding and the structural basis of the agonist and antagonistic effect of certain ligands. We therefore started an exhaustive computational analysis aimed at gaining a better understanding of peptide ligand binding selectivity between the three FPRs and induced conformational changes of agonist and antagonist binding. 

References

  1. Bufe, B., Schumann, T., Kappl, R., Bogeski, I., Kummerow, C., Podgórska, M., Smola, S., Hoth, M., Zufall, F. Recognition of bacterial signal peptides by mammalian formyl peptide receptors: a new mechanism for sensing pathogens. J. Biol. Chem. 2015, 290, 7369-7387.
  2. Chen, T., Xiong, M., Zong, X., Ge, Y., Zhang, H., Wang, M., Won Han, G., Yi, C., Ma, L., Ye, R.D., Xu, Y., Zhao, Q., Wu, B. Structural basis of ligand binding modes at the human formyl peptide receptor 2. Nat. Commun. 2020, 11, 1208.
  3. Zhuang, Y., Liu ,H., Edward Zhou, X., Kumar Verma, R., de Waal, P.W., Jang, W., Xu, T.H., Wang, L., Meng, X., Zhao, G., Kang, Y., Melcher, K., Fan, H., Lambert, N.A., Eric Xu, H., Zhang, C. Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nat. Commun. 2020, 11, 885.