Orthosteric and allosteric action of the C5a receptor antagonists

Liu, Heng1; Kim, Hee Ryung2; Deepak, R. N. V. Krishna3; Wang, Lei1; Chung, Ka Young2; Fan, Hao3; Wei, Zhiyi4; Zhang, Cheng1

2018-06

10.1038/s41594-018-0067-z

NATURE STRUCTURAL ＆ MOLECULAR BIOLOGY   影响因子和分区

1545-9993

1545-9985

The C5a receptor (C5aR) is a G-protein-coupled receptor (GPCR) that can induce strong inflammatory response to the anaphylatoxin C5a. Targeting C5aR has emerged as a novel anti-inflammatory therapeutic method. However, developing potent C5aR antagonists as drugs has proven difficult. Here, we report two crystal structures of human C5aR in ternary complexes with the peptide antagonist Rho Mu Chi 53 and a non-peptide antagonist, either avacopan or Nu DT9513727. The structures, together with other biophysical, computational docking and cell-based signaling data, reveal the orthosteric action of Rho Mu Chi 53 and its effect of stabilizing the C5aR structure, as well as the allosteric action of chemically diverse non-peptide C5aR antagonists with different binding poses. Structural comparison analysis suggests the presence of similar allosteric sites in other GPCRs. We also discuss critical structural features of C5aR in activation, including a novel conformation of helix 8. On the basis of our results, we suggest novel strategies for developing C5aR-targeting drugs.

SCI

英语

NI论文

其他

National Natural Science Foundation of China[31770791] ; National Natural Science Foundation of China[315707410]

Biochemistry & Molecular Biology ; Biophysics ; Cell Biology

Biochemistry & Molecular Biology ; Biophysics ; Cell Biology

WOS:000434470800007

NATURE PUBLISHING GROUP

BIOLOGY & BIOCHEMISTRY

Web of Science

1.Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15260 USA
2.Sungkyunkwan Univ, Sch Pharm, Suwon, South Korea
3.ASTAR, Bioinformat Inst BII, Singapore, Singapore
4.Southern Univ Sci & Technol, Dept Biol, Shenzhen, Peoples R China

Liu, Heng,Kim, Hee Ryung,Deepak, R. N. V. Krishna,et al. Orthosteric and allosteric action of the C5a receptor antagonists[J]. NATURE STRUCTURAL ＆ MOLECULAR BIOLOGY,2018,25(6):472-+.

Liu, Heng.,Kim, Hee Ryung.,Deepak, R. N. V. Krishna.,Wang, Lei.,Chung, Ka Young.,...&Zhang, Cheng.(2018).Orthosteric and allosteric action of the C5a receptor antagonists.NATURE STRUCTURAL ＆ MOLECULAR BIOLOGY,25(6),472-+.

Liu, Heng,et al."Orthosteric and allosteric action of the C5a receptor antagonists".NATURE STRUCTURAL ＆ MOLECULAR BIOLOGY 25.6(2018):472-+.