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Review
. 2021 Apr 20:19:2148-2159.
doi: 10.1016/j.csbj.2021.04.029. eCollection 2021.

Farnesoid X receptor (FXR): Structures and ligands

Longying Jiang  1   2 , Huajun Zhang  2 , Desheng Xiao  1 , Hudie Wei  1   2 , Yongheng Chen  1   2
Affiliations
Review

Farnesoid X receptor (FXR): Structures and ligands

Longying Jiang et al. Comput Struct Biotechnol J. .

Erratum in

Abstract

Farnesoid X receptor (FXR) is a bile acid activated nuclear receptor (BAR) and is mainly expressed in the liver and intestine. Upon ligand binding, FXR regulates key genes involved in the metabolic process of bile acid synthesis, transport and reabsorption and is also involved in the metabolism of carbohydrates and lipids. Because of its important functions, FXR is considered as a promising drug target for the therapy of bile acid-related liver diseases. With the approval of obeticholic acid (OCA) as the first small molecule to target FXR, many other small molecules are being evaluated in clinical trials VSports手机版. This review summarizes the structures of FXR, especially its ligand binding domain, and the development of small molecules (including agonists and antagonists) targeting FXR. .

Keywords: Agonists; Antagonists; Farnesoid X receptor; Ligand binding domain; Structure V体育安卓版. .

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Graphical abstract
Fig. 1
Fig. 1
The importance of FXR in the enterohepatic circulation of bile acids. FXR represses the transcriptional activity of hepatic Cyp7a1 and Cyp8b1 by upregulating the expression of SHP. FXR stimulates the synthesis of the FGF-15/19-FGFR4 pathways to inhibit CYP7A1 and CYP8B1 expression. FXR regulates key genes involved in BA transport, reabsorption, conjugation and detoxification, such as NTCP, BSEP, MDR3 and OSTα/β.
Fig. 2
Fig. 2
Schematic diagram and structure of FXR. (A) Organization of FXR. (B) Schematic diagram of four FXRα protein isoforms. (C) Model structure of FXR-DBD. The EcR-DBD structure (PDB ID: 1R0O) is used to represent the FXR-DBD. (D) Crystal structure of the FXR-LBD/OCA complex (PDB ID 1OSV). The FXR-LBD is shown in greencyan, OCA is in orange and the NcoA peptide is colored magenta. (E) The typical IR1 element. The IR1 sequence is found in the footprintDB database. The IR1 schematic diagram is generated by WebLogo. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Overall structures of FXR in different states. (A) The apo-FXR structure (PDB ID 5Q0K). (B) FXR/CDCA (4QE6). (C) FXR/OCA (1OSV). (D) FXR/Tropifexor (7D42). (E) FXR/Ivermectin (4WVD) (F) FXR/DM175 (4QE8). FXR is colored gray. The regions discussed are colored as follows: H4 (yellow), H11 (olive), H3′ (violet), H12 (lightblue), NcoA (lightpink), NcoR (palecyan). The LBP pocket volumes of FXR are calculated using POCASA. (G) Superposition of different ligand binding patterns. Key protein regions affected by ligand binding are highlighted. The critical polar residues and main hydrophobic residues in the pocket are labeled. The ligands are shown in different colors: CDCA (green), OCA (orange), 7D42 (blue), ivermectin (cyan), DM175 (skyblue). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
Chemical structure of FXR agonists.
Fig. 5
Fig. 5
Chemical structure of FXR antagonists.
Fig. 6
Fig. 6
Structural superposition of OCA with GPBAR1. (A) Structure of INT-777/GPBAR1 complex (7CFN). GPBAR is shown in limon and INT-777 is colored red. (B) Structure of OCA/FXR complex. The hydrogen bonds between OCA (orange) and FXR-LBD (greencyan) are shown as black dashed line. (C) Structural superposition of OCA with GPBAR1. Residues involved in the interactions are labeled and shown as sticks. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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References

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