Intracellular receptors
Under development!!! Signal recognition particle receptor. Water molecules are shown as red spheres. . Receptor for activated C kinase 1Nuclear receptorsThe 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) [1] 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) [2]. PPARγ is involved in transcriptional regulation of glucose and lipid homeostasis [1], and helps regulate adipocyte differentiation [3]. 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 [4]. 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.
Endoplasmic reticulum/Sarcoplasmic reticulum receptorsLigand-gated Calcium channelsInositol 1,4,5-Trisphosphate ReceptorRyanodine receptorSEE ALSO:
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ReferencesReferences
- ↑ 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