Signal transduction

Under development!

• Ligand
• Types of ligands
• Hormones and their receptors
• Hormone
• Growth factors
• Neurotransmitters
• 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^[1].

• 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, , to at the acidic pH prevailing within the lysosome. .
• 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, 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.

and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect.

• Glucocorticoids
• Mineralocorticoids
• Pentaerythritol tetranitrate reductase active site contains the cofactor and the ^[2]. Water molecules are shown as red spheres. .
• Corticosteroid-binding globulin

(hydrocortisone) is a corticosteroid with both glucocorticoid and mineralocorticoid activity and effects.

Glucocorticoids

Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. is a glucocorticoid medication. It is the most potent glucocorticoid and it has not mineralocorticoid potency.

• Glucocorticoid receptor. (1m2z).
• Forkhead box proteins (FOX) are transcription factors involved in regulation of gene expression.^[3]. FOXO1 activation contributes to glucocorticoid-induced beta cell death^[4]. FOX contain a DNA-binding motif (DBD) of 80-100 amino acids having a winged-helix shape.
  • .
  • . Water molecules shown as red spheres.
  • .

• 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^[5]. NCOA1 shows histone acetyltransferase activity and is required for steroid hormone response. NCOA2 is a DNA transcription coactivator with glucocorticoid receptor.
  • .
  • .
  • . Water molecules are shown as red spheres.
  • .
  • .

• Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH^[6]. Mutations in TrxR-2 are associated with familial glucocorticoid deficiency^[7]. Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH^[8]. TrxR-2 is mitochondrial. For more details see User:Sarah Abdalla/Thioredoxin Reductase. TrxR and Trx form an ^[9]. . 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^[10] . PGES is induced by proinflammatory stimuli and down-regulated by anti-inflammatory glucocorticoids^[11]. Microsomal Prostaglandin E synthase (coordinates are from OPM database. The ^[12]. 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 .

• 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^[13]. 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^[14]. MR mutation S810L causes early-onset hypertension^[15]. Inhibition of cardia MR prevents doxorubicin-induced cardiotoxicity^[16]. 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^[17]. The MR ligand aldosterone binds in a (Alpha Helices, Beta Strands , Loops ,Turns). ^[18]. . 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 . 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 which binds intramolecularly the N-terminal FXXFL motif or coactivators with the same motif.^[19] Water molecules are shown as red spheres. (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^[20]. Depletion of HSF-1 is associated with accumulation of pathogenic androgen receptor in neurodegenerative diseases^[21].
• 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^[22].
• 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

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

to human estrogen-related receptor γ. The chemotherapeutic drugs bisphenol and 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, 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

(P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species.

• Progesterone receptor. (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)

.

(5ien)

Calcitriol is the active form of vitamin D pro-hormone.

• Vitamin D receptor (also called calcitriol receptor)

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 (green) binds to receptors in its target cells, controlling the synthesis of many different proteins involved in Ca transport and utilization.

.

. VDR contains 2 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. is replaced with 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 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

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.

MAPK

• 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)

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