Intracellular receptors

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 50: Line 50:
Peroxisome proliferator-activated receptor gamma (<scene name='PPAR-gamma/Ppar_gamma/3'>PPAR</scene>γ) is a protein in the nuclear receptors subfamily. It is one of three isotypes (-α, -β/ δ, and -γ) of [[PPAR]] receptors and has two protein isoforms governed by splice variations, which result in differences in the length of the amino (N)-terminal region (PPARγ1 and PPARγ2). PPARγ is involved in transcriptional regulation of glucose and lipid homeostasis, and helps regulate adipocyte differentiation. It has a <scene name='PPAR-gamma/Binding_pocket/1' target='1'>large binding pocket</scene>, which allows it to interact with a wide array of ligands. <scene name='PPAR-gamma/Interacting_residues/3'>Ligand binding</scene> typically triggers a conformational change of PPARγ, notably in the activation function-2 <scene name='PPAR-gamma/Af-2_domain/2'>(AF-2) domain</scene>, which aids in the recruitment of co-regulatory factors to regulate gene transcription. PPARγ can form a <scene name='PPAR-gamma/Ppar_rxr/3'>heterodimer</scene> with retinoic X receptor alpha (RXRα), a process necessary for most PPARγ-DNA interactions. PPARγ is a molecular target for antidiabetic drugs such as thiazolidinediones (TZDs), which makes the protein a target for Type II Diabetes (T2D) drug research. Due to its involvement in metabolic and inflammatory processes, PPARγ also holds potential for treatments of many metabolic and chronic-inflammatory diseases, such as metabolic syndrome and inflammatory bowel disease, respectively. Errors in PPARγ-related regulation have also been implicated in atherosclerosis and various cancers, like colorectal, breast, and prostate cancers.
Peroxisome proliferator-activated receptor gamma (<scene name='PPAR-gamma/Ppar_gamma/3'>PPAR</scene>γ) is a protein in the nuclear receptors subfamily. It is one of three isotypes (-α, -β/ δ, and -γ) of [[PPAR]] receptors and has two protein isoforms governed by splice variations, which result in differences in the length of the amino (N)-terminal region (PPARγ1 and PPARγ2). PPARγ is involved in transcriptional regulation of glucose and lipid homeostasis, and helps regulate adipocyte differentiation. It has a <scene name='PPAR-gamma/Binding_pocket/1' target='1'>large binding pocket</scene>, which allows it to interact with a wide array of ligands. <scene name='PPAR-gamma/Interacting_residues/3'>Ligand binding</scene> typically triggers a conformational change of PPARγ, notably in the activation function-2 <scene name='PPAR-gamma/Af-2_domain/2'>(AF-2) domain</scene>, which aids in the recruitment of co-regulatory factors to regulate gene transcription. PPARγ can form a <scene name='PPAR-gamma/Ppar_rxr/3'>heterodimer</scene> with retinoic X receptor alpha (RXRα), a process necessary for most PPARγ-DNA interactions. PPARγ is a molecular target for antidiabetic drugs such as thiazolidinediones (TZDs), which makes the protein a target for Type II Diabetes (T2D) drug research. Due to its involvement in metabolic and inflammatory processes, PPARγ also holds potential for treatments of many metabolic and chronic-inflammatory diseases, such as metabolic syndrome and inflammatory bowel disease, respectively. Errors in PPARγ-related regulation have also been implicated in atherosclerosis and various cancers, like colorectal, breast, and prostate cancers.
-
PPARγ is composed of the ligand-independent activation domain (AF-1 region and A/B-domain), a DNA-binding domain (DBD) (C-domain), a hinge region (D-domain), and a ligand-dependent ligand-binding domain (LBD) (E/F-domain and AF-2 region) [5]. The two PPARγ isoforms, PPARγ1 and PPARγ2, differ by only 30 amino acids at the N-terminal end. These added amino acids on PPARγ2 result in increased potency and adipose-selectivity, which makes this protein a key player of adipocyte differentiation [3].
+
PPARγ is composed of the ligand-independent activation domain (AF-1 region and A/B-domain), a DNA-binding domain (DBD) (C-domain), a hinge region (D-domain), and a ligand-dependent ligand-binding domain (LBD) (E/F-domain and AF-2 region). The two PPARγ isoforms, PPARγ1 and PPARγ2, differ by only 30 amino acids at the N-terminal end. These added amino acids on PPARγ2 result in increased potency and adipose-selectivity, which makes this protein a key player of adipocyte differentiation.
-
The <scene name='PPAR-gamma/Lbd/2' target='2'>ligand binding domain</scene> is composed of 13 α helices and 4 short β strands [1]. It has a T-shaped binding pocket with a volume of ~1440 Å3 [1, 6], which is larger than that of most nuclear receptors [7], allowing for interactions with a variety of ligands [8]. The PPARγ LBD is folded into a helical sandwich to provide a binding site for ligands. It is located at the C-terminal end of PPARγ and is composed of about 250 amino acids [5]. Activation by full agonists occurs through hydrogen bond interactions between the S289, H323, Y473, and H449 residues of the PPARγ-LBD [7] and polar functional groups on the ligand which are typically carbonyl or carboxyl oxygen atoms. Agonist binding results in a conformational change of the LBD AF-2 region, which is necessary for coactivator recruitment. This change can either be dramatic or subtle [1], which leads to stabilization of a charge clamp between helices H3 and H12 [9] to aid in associations with the LXXLL (L, leucine; X, any amino acid) motif of the coactivator [1, 10]. Ligand binding of PPARγ is regulated by communication between the N-terminal A/B domain, which is adjacent to the DBD, and the carboxyl-terminal LBD [11].
+
The <scene name='PPAR-gamma/Lbd/2' target='2'>ligand binding domain</scene> is composed of 13 α helices and 4 short β strands. It has a T-shaped binding pocket with a volume of ~1440 Å3, which is larger than that of most nuclear receptors, allowing for interactions with a variety of ligands. The PPARγ LBD is folded into a helical sandwich to provide a binding site for ligands. It is located at the C-terminal end of PPARγ and is composed of about 250 amino acids. Activation by full agonists occurs through hydrogen bond interactions between the S289, H323, Y473, and H449 residues of the PPARγ-LBD and polar functional groups on the ligand which are typically carbonyl or carboxyl oxygen atoms. Agonist binding results in a conformational change of the LBD AF-2 region, which is necessary for coactivator recruitment. This change can either be dramatic or subtle , which leads to stabilization of a charge clamp between helices H3 and H12 to aid in associations with the LXXLL (L, leucine; X, any amino acid) motif of the coactivator. Ligand binding of PPARγ is regulated by communication between the N-terminal A/B domain, which is adjacent to the DBD, and the carboxyl-terminal LBD.
* [[Pioglitazone]] is a selective agonist for Peroxisome Proliferator-Activated Receptor Gamma
* [[Pioglitazone]] is a selective agonist for Peroxisome Proliferator-Activated Receptor Gamma
*[[Liver X receptor]]
*[[Liver X receptor]]

Revision as of 13:00, 19 May 2021

Human androgen receptor ligand-binding domain complex with modulator (PDB code 3b5r)

Drag the structure with the mouse to rotate

References

  1. ↑ Li MJ, Greenblatt HM, Dym O, Albeck S, Pais A, Gunanathan C, Milstein D, Degani H, Sussman JL. Structure of estradiol metal chelate and estrogen receptor complex: The basis for designing a new class of selective estrogen receptor modulators. J Med Chem. 2011 Apr 7. PMID:21473635 doi:10.1021/jm200192y

Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky

Retrieved from "http://52.214.119.220/wiki/index.php/Intracellular_receptors"
Personal tools