Signal transduction

spinqualitylabelsall models Nicotinic Acetylcholine Receptor, PDB code 2bg9 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Under development! Ligand Types of ligands Hormones and their receptors Hormone Growth factors Neurotransmitters Neuropeptides Neuromodulators Receptor Ion channels Chemical communication in arthropods Proton Channels Neuronal Nitric Oxide Synthase (Nos1) is functioning in cell signaling and communication - a vital part of the nervous tissue. Chloride Ion Channel Chloride Intracellular Channel Protein 2 Ivermectin bound to Glu gated chloride channel Membrane Channels & Pumps Ryanodine receptor Lipid signaling: Ceramide Sphingomyelinase (SMase) or sphingomyelin phosphodiesterase is a hydrolase involved in sphingolipid metabolism. It catalyzes the breakdown of sphingomyelin (SM) to phosphocholine and ceramide. Acid-beta-glucosidase or glucosylceramidase is a lysozomal enzyme (EC number 3.2.1.45), which cleaves glucosylceramide to glucose and ceramide. It catalyzes hydrolysis of the sphingolipid, glucosylceramide (GlcCer), to glucose and ceramide at the acidic pH prevailing within the lysosome. Click here to see animation of this reaction. The molecular function of galactosylceramidase is hydrolysis of a O-glycosyl bond to remove galactose from ceramide and other sphingolipids. Sphingosine-1-Phosphate Lysophosphatidic acid receptor#Sphingosine 1-Phosphate Receptor Glucosylceramide Acid-beta-glucosidase Phosphatidylinositol bisphosphate (PIP2) Phosphatidylinositol 4,5-bisphosphate (PIP2) binds to and directly activates inwardly rectifying potassium channels. Inward rectifier KCh. Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1) Phospholipase C beta 3 The Structure of PI3K Epsin Phosphoinositide 3-Kinases PI3K Activation, Inhibition, & Medical Implications Prostaglandins Prostaglandin D synthase Prostaglandin E synthase Cyclooxygenase Prostaglandin-E2 9-reductase Prostaglandin F synthase Leukotriene B4 hydroxydehydrogenase Aldo-keto reductase Endocannabinoids Beta-2 adrenergic receptor Monoglyceride lipase GPR40 Lysophosphatidic acid receptor#Endocannabinoid Receptor 1 Fatty acid amide hydrolase Retinol derivatives Retinal Rhodopsin Rhodopsin Structure and Function The BioMolViz Project Bacteriorhodopsin CRABP I ( Cellular Retinoic Acid Binding Protein ) Retinal dehydrogenase User:Rick H. Cote/PDE6#PDE6: central effector of visual excitation in retinal rod and cone photoreceptors Transducin Pikachurin Retinoid isomerohydrolase Retinoic acid Retinoic acid receptor Cellular retinoic acid-binding protein CRABP I ( Cellular Retinoic Acid Binding Protein ) NK cell receptor Retinoid X receptor RA Mediated T-reg Differentiation PPAR-gamma Student Project 2 for UMass Chemistry 423 Spring 2015 Aldehyde dehydrogenase Steroid Hormones and their receptors This large and diverse class of steroids are biosynthesized from isoprenoids and structurally resemble cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens. Vitamin D derivatives are a sixth closely related hormone system with homologous receptors. They have some of the characteristics of true steroids as receptor ligands. For example, estradiol is an important estrogen steroid hormone in both women and men. It is a typical steroid with core four-ring system (ABCD), composed of 17 carbon atoms. Corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes. Prednisone and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect. Glucocorticoids Mineralocorticoids Pentaerythritol tetranitrate reductase active site contains the cofactor FMN and the substrate steroid prednisone. Water molecules are shown as red spheres. Whole active site. Corticosteroid-binding globulin Cortisol (hydrocortisone) is a corticosteroid with both glucocorticoid and mineralocorticoid activity and effects. Glucocorticoids Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. Dexamethasone is a glucocorticoid medication. It is the most potent glucocorticoid and it has not mineralocorticoid potency. Glucocorticoid receptor. Human glucocorticoid receptor ligand-binding domain bound to dexamethasone (1m2z). Forkhead box proteins (FOX) are transcription factors involved in regulation of gene expression.. FOXO1 activation contributes to glucocorticoid-induced beta cell death. FOX contain a DNA-binding motif (DBD) of 80-100 amino acids having a winged-helix shape. Human FoxO1 DNA-binding domain with DNA, Ca+2 and Cl- ions. Ca coordination site. Water molecules shown as red spheres. Cl coordination site. Nuclear receptor coactivator (NCOA) is a protein recruited by nuclear receptors in order to enhance or repress DNA transcription. NCOA is involved in coactivation with transcription factors. NCOA1 shows histone acetyltransferase activity and is required for steroid hormone response. NCOA2 is a DNA transcription coactivator with glucocorticoid receptor. NCOA/STAT6 transactivator domain LXXLL peptide interactions. 1st Iod coordination site. 2nd Iod coordination site. Water molecules are shown as red spheres. 3th and 4th Iod coordination sites. 5th Iod coordination site. Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH. Mutations in TrxR-2 are associated with familial glucocorticoid deficiency. Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH. TrxR-2 is mitochondrial. For more details see User:Sarah Abdalla/Thioredoxin Reductase. TrxR and Trx form an intramolecular Cys-Cys bond. FAD binding site. Water molecules are shown as red spheres. Microsomal Prostaglandin E synthase (PGES) converts cyclooxygenase (COX)-derived prostaglandin to PGE2. It is membrane-associated and belongs to the microsomal glutathione S-transferase family. PGES is preferentially linked with the inducible COX-2 . PGES is induced by proinflammatory stimuli and down-regulated by anti-inflammatory glucocorticoids. Microsomal Prostaglandin E synthase is membrane-associated (coordinates are from OPM database. The anti-inflammatory inhibitor binds to PGES in a pocket above the glutathione and interacts with various side-chains of a helix. Water molecules are shown as red spheres. Mineralocorticoids Mineralocorticoids are a class of corticosteroids. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mineralocorticoid is aldosterone. Mineralocorticoid receptor (MR) in epithelial cells is activated by the mineralocorticoid hormone aldosterone promoting renal sodium retention and potassium excretion. It is nuclear receptor. In non epithelial cells MR is activated by cortisol. MR is exposed to many steroids including cortisol, cortisone and progesterone, however, aldosterone and deoxycorticosterone are its physiological ligands. MR mutations are the principal cause of renal pseudohypoaldosteronism. MR mutation S810L causes early-onset hypertension. Inhibition of cardia MR prevents doxorubicin-induced cardiotoxicity. MR is an important proadipogenic transcription factor that may mediate aldosterone and glucocorticoid effects on adipose tissue development and hence on obesity and development of metabolic syndrome. The MR ligand aldosterone binds in a fully enclosed pocket, contacting residues with six α-helices and a β-turn (Alpha Helices, Beta Strands , Loops ,Turns). It forms hydrogen bonds with 4 MR residues. Whole binding site. Water molecules are shown as red spheres. Angiotensin-Converting Enzyme, Renin-Angiotensin-Aldosterone System. Hydroxysteroid dehydrogenase Sex steroids Androgens An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. The major androgen in males is testosterone. It is the primary sex hormone and anabolic steroid in males. It is a steroid from the androstane class. It exerts its action through binding to and activation of the androgen receptor. Androgen receptor. Ligand binding domain (LBD) containing an active site which binds intramolecularly the N-terminal FXXFL motif or coactivators with the same motif. Water molecules are shown as red spheres. Human androgen receptor bound to testosterone (2ylo). Heat shock factor (HSF) are transcriptional activators of heat shock genes. HSF bind to heat shock sequence elements throughout the genome with a consensus array of three oppositely oriented sequence AGGAN and activate transcription. Each HSF monomer contains one C-terminal and 3 N-terminal leucine zippers. Two sequences flanking the N-terminal leucine zippers contain the consensus nuclear localization signal (NLS). The DNA-binding domain (DBD residues 193-281) of HSF lies in the N-terminal of the first NLS region. Depletion of HSF-1 is associated with accumulation of pathogenic androgen receptor in neurodegenerative diseases. Cellular retinoic acid-binding protein (CRABP); Epididymal RABP (ERABP) is an androgen-dependent RABP present in the lumen of the epididymis believed to be involved in sperm maturation. ERABP binds specifically all-trans- and 9-cis-RA. Aromatase. The primary function of aromatase is to produce estrogens by aromatizing androgens. Aromatase is the only known enzyme in vertebrates capable of catalyzing the aromatization of a six-membered ring. Student Project 1 for UMass Chemistry 423 Spring 2015. Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, histone demethylase, androgen receptor, and histone demethylase signaling pathways and is involved in ovary and prostate cancer. A lot of PRK1 is expressed in cases of ovarian serous carcinoma. Finasteride Zolinza (Vorinostat) Hydroxysteroid dehydrogenase, 17-β HSD is involved in the conversion of androstenedione to testosterone. Aromatase converts androstenedione to estrogen and testosterone to estradiol. Lipids: structure and classification Cytochrome P450 3A4 (CYP3A4) Estrogens There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy. Estrogen receptor Click here to see the difference between conformations of estrogen receptor α complexed with raloxifene and a corepressor peptide (morph was taken from Gallery of Morphs of the Yale Morph Server). Estrogen-related receptor Tamoxifen and the Estrogen Receptor/Tamoxifen and the Estrogen-related receptor Binding of nuclear receptor corepressor 2 peptide and 4-hydroxytamoxifen to human estrogen-related receptor γ. The chemotherapeutic drugs bisphenol and tamoxifen are nestled between 4 alpha helices in the ERR active site. Estrogen sulfotransferase Aromatase Finasteride Estrone Estrogen receptor 3D structures Estrone sulfatase Sulfatase 3D structures ABC transporter 3D structures ABCG2 multidrug transporter Substrates, such as estrone sulfate, form hydrogen bonds and stacking interactions with residues from each subunit in Cavity 1 of ABCG2 multidrug transporter. Hydroxysteroid dehydrogenase Hydroxysteroid dehydrogenase 3D structures Prostaglandin F synthase Estradiol Lipids: structure and classification Estrogen receptor Ivan Koutsopatriy estrogen receptor Estradiol 17-beta-dehydrogenase Student Project 10 for UMass Chemistry 423 Spring 2015 Aromatase Sulfotransferase ATPase family AAA domain-containing protein 2 Hypoxia-Inducible Factors Estriol Cytochrome P450 3D structures: 1x8v - MtP450 CYP51 (mutant)+estriol Estetrol 3l03 - Crystal Structure of human Estrogen Receptor alpha Ligand-Binding Domain in complex with a Glucocorticoid Receptor Interacting Protein 1 Nr Box II peptide and Estetrol (Estra-1,3,5(10)-triene-3,15 alpha,16alpha,17beta-tetrol) Progestogens Progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. Progesterone receptor. Human progesterone receptor ligand-binding domain bound with progesterone (1a28). Water molecules are shown as red spheres. Progesterone is a negative allosteric modulator of nicotinic acetylcholine receptors, and a potent antagonist of the mineralocorticoid receptor. Hydroxysteroid dehydrogenase, 20-α HSD is involved in the control of progesterone level in pregnancy of mice. 17-β HSD is involved in the conversion of androstenedione to testosterone. Vitamin D derivatives; secosteroids (open-ring steroids) Vitamin D. 25-hydroxy-cholecalciferol (25-D3); 25-hydroxyvitamin D3 (5ien) Calcitriol is the active form of vitamin D pro-hormone. Vitamin D receptor (also called calcitriol receptor) Vitamin D receptor (VDR) 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 vitamin D hormone (green) binds to receptors in its target cells, controlling the synthesis of many different proteins involved in Ca transport and utilization. Vitamin D hormone binding site. Vitamin D hormone is located in deep pocket. VDR contains 2 domains: a ligand binding domain (LBD), that binds to the hormone (grey) and DNA-binding domain (DBD) 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 serine is mutated it is replaced with a glycine 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. Serine is replaced with aspartic acid when mutated creating a negative charge. The negative charge at the residue inhibits DNA binding which cause a downregulation of VDR activity. VDR needs DNA binding in order for it to be activated which is only possible with a serine residue. 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 α,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. It was shown that the synthetic analogue (20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D(3) (2a) acts as a 1α,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 1α,25(OH)(2)D(3), 2α-methyl-1α,25(OH)(2)D(3), or 2a, a novel analogue, 2α-methyl-(20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D(3) (4a) was designed, in order to increase its transactivation potency. Signaling Pathways: ABA Signaling Pathway ABA Signaling Pathway PYR/PYL/RCAR family of ABA receptors Protein Phosphatase 2C ABA-regulated SNRK2 Protein Kinase MAPK/ERK pathway Mitogen-activated protein kinase Mitogen-activated protein kinase kinase Mitogen-activated protein kinase kinase kinase Michael Roberts/BIOL115/ERK2 p38 MAPK (UMass Chem 423 Student Projects 2011-2) Protein Kinases: Calcium-dependent protein kinase Calcium/Calmodulin-dependent protein kinase Eukaryotic Protein Kinase Catalytic Domain Interleukin-1 receptor-associated kinase Tyrosine kinase Receptor tyrosine kinases Tyrosine kinase Janus kinase or tyrosine-protein kinase JAK (JAK) are nonreceptor tyrosine kinases which transduces cytokine-mediated signals via the JAK-STAT pathway. The JAK-STAT pathway transmits signals through the cell membrane to DNA promoters thus causing transcription. Protein kinase C Protein kinase C The sensitization of TRPV1 is thought to be connected to phosphorylation by protein kinase C and the cleavage of PIP2. CAMP-dependent protein kinase CAMP-dependent protein kinase CAMP Dependent Protein Kinase, Catalytic Subunit Protein Kinase A Chemotaxis: Chemotaxis protein, Histidine Kinase (HK) CheA relays signals from the transmembrane chemoreceptors (methyl-accepting chemotaxis proteins/MCPs) to regulate bacterial chemotaxis. Molecular Playground/Cytoplasmic domain of chemoreceptor of Thermotoga maritima Molecular Playground/Bacterial Chemotaxis Receptors Molecular Playground/cytoplasmic domain of a serine chemotaxis receptor Methyl-accepting chemotaxis protein Mechanotransduction: Fibronectin, Laminin, and Collagen can bind to receptors (integrins). CD44 is a glycoprotein involved in cell-cell interactions. CD44 is a receptor of hyaluronic acid (HA). Mechanosensitive channels are involved in touch, hearing, and in maintaining osmotic balance. Thermoception Heat Shock Proteins Transient receptor potential channels Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1) Voltage-gated channels Voltage-gated calcium channels Voltage-gated calcium channel Cav1.1 complex Potassium Channel Potassium channel toxin Visual phototransduction Light is detected by rhodopsin in rod and cone cells. Rhodopsin#Visual Signal Transduction Rhodopsin Structure and Function Photoreceptor pigments Retinal (in rhodopsin). Rhodopsin#Retinal Chromophore of Rhodopsin and Rhodopsin#Photoisomerization of 11-cis Retinal. Flavin (in cryptochrome). Cryptochrome 4 and JMS/cryptochrome. Circadian clock Circadian clock protein Circadian Clock Protein KaiC Period circadian protein Protein phosphatases: Protein Phosphatase 2C ABA-regulated Protein Phosphatase 2C Second messengers cAMP is second messenger Adenylyl cyclase (ADCY, EC number 4.6.1.1), also known as adenylate cyclase, is an enzyme which catalyzes the cyclization of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). Catabolite gene activator protein CAMP-dependent protein kinase CAMP-dependent protein kinase CAMP Dependent Protein Kinase, Catalytic Subunit Protein Kinase A IP3 is second messenger Phospholipase C and PLC beta 3 Gq Receptors that activate this pathway (Phospholipase C) are mainly G protein-coupled receptors coupled to the Gαq subunit, including: 5-HT2 serotonergic receptors (5-hydroxytryptamine receptor#Structural highlights/Specific Function of 5-HT2B). α1 adrenergic receptors Calcitonin receptors Histamine H1 receptor. The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. The H1 receptor is linked to an intracellular G-protein (Gq) that activates phospholipase C and the inositol triphosphate signaling pathway. When a ligand binds to a G protein-coupled receptor that is coupled to a Gq heterotrimeric G protein, the α-subunit of Gq can bind to and induce activity in the PLC isozyme PLC-β, which results in the cleavage of PIP2 into IP3 and DAG. Metabotropic glutamate receptor 1 and metabotropic glutamate receptor 5 belong to group I and activate phospholipase C. For details see Metabotropic glutamate receptor 5. M1, M3, and M5 muscarinic receptors. Muscarinic acetylcholine receptors (mAChR) contain 5 subtypes M1-M5. Subtypes M1, M3, M5 activate phospholipase C which leads to activation of protein kinase C. Inositol 1,4,5-Trisphosphate Receptor Paracrine signaling: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily Fibroblast growth factor and Fibroblast growth factor receptor (FGFR). FGFR belongs to Receptor tyrosine kinases, class V. Sonic Hedgehog Sonic Hedgehog Protein patched homolog 1 (Ptch1) acts as receptor of Sonic Hedgehog protein (Shh) which is involved in formation of embryonic structures. Ca2+ signalling processes Inositol 1,4,5-Trisphosphate Receptor Calcium-dependent protein kinase Calcium/Calmodulin-dependent protein kinase Protein kinase C H+/K+-ATPase signal pathway (acetylcholine, histamine, and gastrin) activates the pump in order to move the vesicles toward the lumen. Esomeprazole and H+/K+ - ATPase Interaction Proton pump Signal transducing adaptor proteins (STAPs) GRB, Growth factor receptor-bound protein and Grb10 SH2 Domain. MyD88, TIR domain-containing adapter protein. GTPase GTPase HRas. The Mitogen-activated protein kinase cascade MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis. Mitogen-activated protein kinase Mitogen-activated protein kinase kinase Mitogen-activated protein kinase kinase kinase Michael Roberts/BIOL115/ERK2 p38 MAPK (UMass Chem 423 Student Projects 2011-2) Inflammatory response Aspirin Effects on Cyclooxygenase Cyclooxygenase Interleukin-10 YKL-40 Toll-like Receptors Phospholipase A2 C-X-C motif chemokine Cytokine receptors Allostery Hemoglobin Thrombin Molecular Playground/Caspase-7 Dynamics RNase A Oligomers ATPase ATPase

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