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Signal recognition particle receptor
. Water molecules are shown as red spheres.
.
Receptor for activated C kinase 1
Nuclear receptors
The
The .
(PDB entry 1dkf).
The Ligand binding domain for each piece of the dimer has a nearly identical structure of an . These alpha helices form a total of 12 domains per protein (referred to as H1-12), with an additional 2 beta sheets as well. Additionally, the α-helical sandwich formed has been shown to bind All-Trans Retinoic Acid (ATRA), the isomer of RA used by the body. Both monomers contain two regions of activity, the and the .
When RARα/RXRα proteins form a heterodimer, the overall structure of the larger dimer is comparable to that of an RXRα homodimer, likely due to the many similarities these two molecules share. RARα and RXRα rely on residues from the H7, H8, H9, H10, L8-9, and L9-10 domains of both molecules to form the . The sequence identity between the two molecules on the dimer interface is 0.33, demonstrating that 33% of the interacting residues are homologous between the different proteins.
The residues of α that are interacting in the heterodimer are as follows:
Hydrophobic residues: L356, F374, P375, L378, M379, I381 and A389 (yellow);
Negatively charged residues: D338, D349, E353, E357, D383, and E393 (red);
Positively charged residues: K360, R364, H372, K376, K380, and R385 (blue);
Hydrophilic residues: Q315, Q352, T382, and S386 (green).
The residues of α that are interacting in the heterodimer are as follows:
Hydrophobic residues: Y402, P417, F420, A421, L424, L425, L427, P428, A429, and L435 (yellow);
Negatively charged residues: E357, D384, E395, E399, E406, and E439 (red);
Positively charged residues: R353, K361, R398, K410, K422, R426, R431, and K436 (blue);
Hydrophilic residues: S432 (green).
Upon binding of the ligand ATRA in the cytoplasm, RARα and RXRα form a heterodimer and alter the C-terminals on domain H12 of both subunits in a manner that allows them to change the conformation of their DNA binding domains. The two proteins have 29% identity in their .
For the ligand used in RARα crystallization, BMS614, 21 primarily hydrophobic residues form the . BMS614 is not the natural ligand for this molecule, but acts as an more stable agonist for crystallization. The largest difference between BMS614 and ATRA upon binding to the pocket are at Ile 412, where BMS614 pushes much closer to the amino acid than ATRA does. Residues that form the binding pocket are found on H1, H3, H5, H11, L6-7, and L11-12 on RARα.
The between RARα, RARβ and RARγ are present in this area:
Residue 270: α:Ile β:Ile γ:Met; Residue 232: α:Ser β:Ala γ:Ala; Residue 395: α:Val β:Val γ:Ala
The is comprised of 16 primarily hydrophobic residues, found on the H3, H5, H7, H11, and L11-12 domains. The ligand used in the crystal, Oleic Acid, is similar to RA, and RA is capable of binding to the RXRα pocket.
(PDB entry 1by4).
When RXRα homodimers assemble on DNA, they form a four poplypeptide complex assembled via head to tail interactions along DR-1 repeated sequences. The
structures of the polypeptides sit in the major grooves of the DNA chain, allowing for interaction with specific bases, giving a sequence specificity for the protein. The two do not alter their configuration upon DNA binding, but are used to guide the DNA into the correct position. Upon binding to DNA, the C-terminal end of the protein, referred to as the alters its conformation from alpha helical to an extended conformation. This extended conformation allows Glu74 to move away from the DNA binding pocket and moves it so it interacts with the Zn(II) domain of the next polypeptide.
RXRα homodimers preferrentially assemble on DR-1 repeat sequences. DR-1 sequences are composed of an AGGTCA tandem repeat, with a single nucleotide spacer in between the repeats. Only Lys22, Lys26, Glu19 and Arg27 interact with the DNA bases directly. interact with the phosphate backbone of the DNA molecule, making sure it is in position for base recognition.
RXRα homodimers have also been shown to assemble on DR-2 tandem repeats, sequences with the same organization as DR-1, but with two nucleotides as a spacer. The DNA interaction is similar with DR-2 repeats, just spaced further apart.
Peroxisome proliferator-activated receptor gamma (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 , which allows it to interact with a wide array of ligands. typically triggers a conformational change of PPARγ, notably in the activation function-2 , which aids in the recruitment of co-regulatory factors to regulate gene transcription. PPARγ can form a 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). 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 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.
The of PPARγ is a groove created by hydrophobic residues of the H3, H3’, H4, and H12 helices. Stabilization of the AF-2 domain is important for coactivator interactions, and is achieved through ligand binding. Upon agonist binding, coactivators and other chromatin-remodeling cofactors, like histone deacetylases, are recruited and transcription is activated. Coactivators can be regulated at the transcriptional and post-transcriptional levels, as well as by protein-kinase cascades. PPARγ can actively silence genes it is bound to by recruiting a corepressor in the absence of a ligand. Once this occurs, an antagonist binds to stabilize the AF-2 region, preventing interactions with coactivators and activation of transcription. Corepressor binding creates a three-turn α-helix corepressor motif important for preventing the AF-2 domain from assuming an active conformation. Common coactivators of PPARγ include CBP/p300, the SRC family, and TRAP220. Common corepressors include SMART, NCoR, and RIP140.
. LXR in the LXR/retinoic X receptor β heterodimer in a hydrophobic .
of human FXR ligand-binding domain (deeppink) complex with non-steroidal agonist, nuclear receptor coactivator 1 peptide (cyan) and sulfate ions (3ruu).
is a transcription factor. Upon binding to vitamin D, VDR forms a heterodimer with retinoid-X receptor and binds to hormone response receptors on DNA causing gene expression. The (in green) binds to receptors in its target cells, controlling the synthesis of many different proteins involved in calcium transport and utilization. . . VDR contains two domains: a , that binds to the hormone (grey) and that binds to DNA (green and blue are 2 same VDR structures). It pairs up with a similar protein, 9-cis retinoic acid receptor (RXR), and together they bind to the DNA, activating synthesis in some cases and repressing it in others.
When is mutated it is replaced with a which results in an inhibition of transcriptional activation. When transcription is inhibited it results in p53 accumulation, which activates and promotes p53 translocation into mitochondria leading to apoptosis. Transcription inhibition is useful in cancer patients and so can be used as treatment option. These are the outcomes of the mutation, with the research still in the process to find the potential cure for tumors.
is replaced with when mutated creating a negative charge. The negative charge at the residue inhibits DNA binding which cause a down – regulation of VDR activity. VDR needs DNA binding in order for it to be activated which is only possible with a serine residue. Research is still continuing to find a therapeutic cause for this mutation.
The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. In the article, "Structure-function relationships and crystal structures of the vitamin D receptor bound 2 alpha-methyl-(20S,23S)- and 2 alpha-methyl-(20S,23R)-epoxymethano-1 alpha,25-dihydroxyvitamin D3" by Antony, P. et al, they showed that acts as a 1alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1alpha,25(OH)(2)D(3), 2alpha-methyl-1alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2alpha-methyl-(20S,23S)-epoxymethano-1alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.
which is used in testing tuberculosis.
. Hydrophobic, Polar. Water molecules are shown as red spheres. . The ligand-binding residues are conserved in the 3 classes of RXR.
of estrogen receptor α complexed with raloxifene and a corepressor peptide (morph was taken from Gallery of Morphs of the Yale Morph Server).
Endoplasmic reticulum/Sarcoplasmic reticulum receptors
Ligand-gated Calcium channels
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