Structural Basis for Bile Acid Binding and Activation of the Nuclear Receptor FXR

Mi, Li-Zhi; Devarakonda, Srikripa; Harp, Joel M.; Han, Qing; Pellicciari, Roberto; Willson, Timothy M.; Khorasanizadeh, Sepideh; Rastinejad, Fraydoon

doi:10.1016/s1097-2765(03)00112-6

Cited by 275 publications

(338 citation statements)

References 26 publications

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“…The structure of human FXR in complex with MFA-1 closely resembles the structures of rat and human FXR reported (24,25), including the presence of a unique helix (helix 6) that replaces a ␤-turn structure seen in many other NHRs (Fig. S3).…”

Section: Resultssupporting

confidence: 54%

“…In this activated receptor structure, helix 12, also referred to as the activation function-2 domain (AF-2), is packed tightly against the body of the LBD in a manner similar to that observed in complexes with bile acids and fexaramine. In this structure, the binding of SRC-1 coactivator peptide to the receptor is extremely similar to the binding of the GRIP-1 peptide to rat FXR in response to bile acid binding (25) and therefore will not be discussed in detail here (Fig. S4).…”

Section: Resultsmentioning

confidence: 99%

“…5A). The observation that the steroid ring system adopts an orientation opposite to that seen with bile acids is somewhat surprising based on previous suggestions that FXR uses shape discrimination to preferentially bind bile acids over conventional steroids (25). The current results suggest that shape discrimination is not the only feature of the receptor dictating the binding mode of steroids to FXR, because MFA-1 also lacks the cis linkage between the A and B rings that is a unique feature of the bile acids (25), yet it is still bound efficiently by the receptor.…”

Section: Mfa-1 Binds In a Flippedmentioning

confidence: 99%

“…The observation that the steroid ring system adopts an orientation opposite to that seen with bile acids is somewhat surprising based on previous suggestions that FXR uses shape discrimination to preferentially bind bile acids over conventional steroids (25). The current results suggest that shape discrimination is not the only feature of the receptor dictating the binding mode of steroids to FXR, because MFA-1 also lacks the cis linkage between the A and B rings that is a unique feature of the bile acids (25), yet it is still bound efficiently by the receptor. Our results, coupled with the fact that the nonpolar surfaces of MFA-1 and bile acids are sandwiched between hydrophobic layers of residues in the receptor that are unlikely to provide binding specificity per se, makes it tempting to speculate that FXR does not discriminate among steroid rings and their binding orientation but rather uses other elements of the binding pocket to select ligands.…”

Section: Mfa-1 Binds In a Flippedmentioning

confidence: 99%

“…The binding of coactivators to the receptor is mediated by nuclear receptor interaction domains (NIDs) on the proteins that contain a conserved LXXLL sequence, and short peptides containing these elements are sufficient for recapitulating these binding interactions (22,23). Before this work, crystal structures of the rat and human FXR LBDs were determined in complex with bile acids and a synthetic ligand, respectively (24,25). We report here the identification of a potent synthetic FXR agonist designated Merck FXR agonist #1 (MFA-1).…”

mentioning

confidence: 99%

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Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

Soisson

Parthasarathy²,

Adams³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-Å resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.NR1H4 ͉ bile acid receptor ͉ nuclear receptor ͉ x-ray crystallography T he farnesoid X receptor (FXR) plays key roles in regulating cholesterol and bile acid homeostasis (1-4). Central to this function is the ability of bile acid-activated FXR to downregulate the expression of Cyp7a (1, 5, 6), the rate-limiting step in the liver for the conversion of free cholesterol to bile acids, and the up-regulation of the bile salt excretion pump (BSEP), which functions to pump excess bile acids into the gall bladder for eventual fecal excretion (7). Treatment of ob/ob and db/db mice with the synthetic FXR agonist GW4064 significantly improves hypercholesterolemia (8) and lowers free fatty acids (9, 10) and triglyceride levels (11). Additional research has shown that fxr Ϫ/Ϫ mice show insulin resistance and impaired glucose tolerance (8,10,12), and that expression of constitutively active FXR in the liver results in hypoglycemia (10). Similarly, treatment with GW4064 increases insulin sensitivity in ob/ob and db/db mice (8, 10). As such, FXR agonists may have utility in treating metabolic syndrome, a clustering of cardiovascular risk factors characterized by dyslipidemia (elevated triglyceride and low HDL levels), insulin resistance, and poor glucose regulation. Several excellent reviews have summarized the current state of FXR understanding (13,14) and help build the case for the development of FXR modulators for the treatment of diabetes and metabolic syndrome (15).FXR belongs to the lar...

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Section: Resultssupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: Mfa-1 Binds In a Flippedmentioning

confidence: 99%

Section: Mfa-1 Binds In a Flippedmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

Soisson

Parthasarathy²,

Adams³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Docking and Scoring in Drug Discovery

Spyrakis

Cozzini

Kellogg

2010

Burger's Medicinal Chemistry and Drug Discovery

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The rational development of new lead compounds requires good understanding of the relationship between all the actors involved in a binding event (protein, ligand, water, metal ions, cofactors, etc.). Computational methods attempt to reproduce and predict the behavior of nature even though this can be very difficult. The docking/scoring paradigm is probably the most widespread and potentially useful computer‐aided technique used in the discovery of new drugs. This paradigm can be analyzed as the sum of a “geometric” problem, that is, the implementation of algorithms to find the possible positions of a ligand in a receptor cavity, and a “chemistry” problem, that is, the evaluation of the solution list using good and realistic energy functions. In this chapter, we deal with the panorama of docking and scoring approaches and the related software packages. After a general introduction, some basic principles about the goodness and limits of experimental data used for computational simulations are described. Then an exhaustive examination of the most common docking methods and packages is carried out followed by an analysis of scoring functions developed to date, including the evolving consensus scoring approach. Next, several problems with the paradigm and their state‐of‐the‐art partial solutions are discussed, including active site water, ionization states, tautomerization, flexibility, and the probability of more than one “correct” solution. Particular attention is paid for the upside and the downside of the problem in a short user guide for the docking and scoring beginner, followed by a conclusions and outlook.

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Nuclear Hormone Receptor Medicinal Chemistry

Cheng

Kick

Mukherjee

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter will be focused on recent advances in the medicinal chemistry of agonist, antagonist, and modulator ligands of selected nuclear hormone receptors (NHRs) that are of special interest in the metabolic diseases therapeutic area (diabetes, obesity and dyslipidemia/atherosclerosis). These NHRs include established biological targets such as the peroxisome proliferator‐activated receptors (PPARs), the liver X receptors (LXRs), and the farnesoid X receptors (FXRs), for which ligands have reached either clinical development or have been approved for clinical usage. Other more recent targets of interest to metabolic diseases include HNF and Rev‐erb.

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Structural Basis for Bile Acid Binding and Activation of the Nuclear Receptor FXR

Cited by 275 publications

References 26 publications

Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

Docking and Scoring in Drug Discovery

Nuclear Hormone Receptor Medicinal Chemistry

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