Abstract:
:Transmembrane domain 6 of the muscarinic acetylcholine (ACh) receptors is important in ligand binding and in the conformational transitions of the receptor but the roles of individual residues are poorly understood. We have carried out a systematic alanine-scanning mutagenesis study on residues Tyr381 to Val387 within the binding domain of the M(1) muscarinic ACh receptor. The seven mutations were then analyzed to define the effects on receptor expression, agonist and antagonist binding, and signaling efficacy. Tyr381Ala produced a 40-fold reduction in ACh affinity and a 50-fold reduction in ACh-signaling efficacy. Leu386Ala had similar but smaller effects. Asn382Ala caused the largest inhibition of antagonist binding. The roles of the hydroxyl group and benzene ring of Tyr381 were probed further by comparative analysis of the Tyr381Phe and Tyr381Ala mutants using three series of ligands: ACh analogs, azanorbornane- and quinuclidine-based ligands, and atropine analogs. These data suggested that the hydroxyl group of Tyr381 is primarily involved in forming hydrogen bond interactions with the oxygen atoms present in the side chain of ACh. We propose that this interaction is established in the ground state and preserved in the activated state of the receptor. In contrast, the Tyr381 benzene ring may form a cation-pi interaction with the positively charged head group of ACh that contributes to the activated state of the receptor but not the ground state. However, the hydroxyl group and benzene ring of Tyr381 both participate in interactions with azanorbornane- and quinuclidine-based ligands and atropine analogs in the ground state as well as the activated state of the receptor.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Ward SD,Curtis CA,Hulme ECdoi
10.1124/mol.56.5.1031keywords:
subject
Has Abstractpub_date
1999-11-01 00:00:00pages
1031-41issue
5eissn
0026-895Xissn
1521-0111journal_volume
56pub_type
杂志文章abstract::Many human cancers show constitutive or amplified expression of the transcriptional regulator and oncoprotein Myc, making Myc a potential target for therapeutic intervention. Here we report the down-regulation of Myc activity by reducing the availability of Max, the essential dimerization partner of Myc. Max is expres...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.054858
更新日期:2009-09-01 00:00:00
abstract::We reported previously that protein associated with Myc (PAM) interacts with the C2 domain of type V adenylyl cyclase (ACV-C2) and that purified PAM is a potent inhibitor of Galphas-stimulated ACV activity (J Biol Chem 276:47583-47589, 2001). The present study was conducted to identify the region in PAM that inhibits ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.005355
更新日期:2005-01-01 00:00:00
abstract::The in vitro binding of [3H]LY354740, the first high affinity group II-selective metabotropic glutamate (mGlu) receptor radioligand, was characterized in rat cortical, hippocampal, and thalamic membranes as well as in rat brain sections. [3H]LY354740 binding was saturable in all regions investigated. Nonspecific bindi...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-02-01 00:00:00
abstract::Exposure to hepatitis C virus (HCV) can lead to the development of cirrhosis and hepatocellular carcinoma. To examine the effects of long-term HCV infection on hepatic cytochrome P450 1A1 (CYP1A1) expression and function, we used a human hepatoma cell line expressing the HCV subgenomic replicon (Huh.8) to evaluate CYP...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.024125
更新日期:2006-09-01 00:00:00
abstract::15-Deoxy delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an activator of peroxisome proliferator-activated receptor (PPAR)-gamma and -delta, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the ma...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.009449
更新日期:2005-07-01 00:00:00
abstract::Herpes simplex virus type 1 (HSV-1) encodes a thymidine kinase (TK) that markedly differs from mammalian nucleoside kinases in terms of substrate specificity. It recognizes both pyrimidine 2'-deoxynucleosides and a variety of purine nucleoside analogs. Based on a computer modeling study and in an attempt to modify thi...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.6.1326
更新日期:2000-12-01 00:00:00
abstract::Ethanol (ETOH) can cause apoptotic death of neurons by depleting GSH with an associated increase in oxidative stress. The current study illustrates a means to overcome this ETOH-induced neurotoxicity by enhancing GSH through boosting Nrf2, a transcription factor that controls GSH homeostasis. ETOH treatment caused a s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.073262
更新日期:2011-12-01 00:00:00
abstract::The 5-hydroxytryptamine3 receptor 5-HT3R has been implicated in gut and cardiac motility and in behavioral disorders. Characteristics of 5-HT3Rs appear to be heterogeneous among species, but human 5-HT3R cDNA has not been identified. We isolated a cDNA encoding 5-HT3R from human hippocampus. The mouse 5-HT3R gene has ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-09-01 00:00:00
abstract::KARs, new semisynthetic antitumor bis-indole derivatives, were found to be inhibitors of tubulin polymerization with lower toxicity than vinblastine or vincristine, used in chemotherapy. Here, we compare the effect of KARs with those of vinblastine and vincristine on cell viability, cell proliferation, and cell cycle ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.60.6.1235
更新日期:2001-12-01 00:00:00
abstract::Carbachol is 100 times more potent for inhibiting cyclic AMP formation than for stimulating phosphoinositide (PI) hydrolysis in chick heart cells. To determine whether this reflects differences in agonist affinity of the receptor(s) coupled to the two responses, we measured these functional responses following removal...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-12-01 00:00:00
abstract::In this work, we evaluate the structural differences of transmembrane helix 3 in rhodopsin and the 5-hydroxytryptamine 1A (5-HT1A) receptor caused by their different amino acid sequence. Molecular dynamics simulations of helix 3 in the 5-HT1A receptor tends to bend toward helix 5, in sharp contrast to helix 3 in rhodo...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.1.15
更新日期:2002-07-01 00:00:00
abstract::Obesity is now recognized as a rapidly increasing worldwide threat to health, largely as a result of causing diabetes. Thus, considerable efforts are underway in the pharmaceutical industry to find drugs to treat this condition. Target validation in various academic and industrial laboratories has revealed a number of...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.106.026104
更新日期:2006-09-01 00:00:00
abstract::The clinical abuse of methamphetamine (METH) is a major concern because it can cause long-lasting neurodegenerative effects in humans. Current concepts of the molecular mechanisms underlying these complications have centered on the formation of reactive oxygen species. Herein, we provide cDNA microarray evidence that ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.5.1124
更新日期:2002-05-01 00:00:00
abstract::Adult guinea pig hippocampal membranes contain two 5-hydroxytryptamine (5-HT) receptors positively coupled with an adenylate cyclase. One is a typical 5-HT1A receptor and the second is a nonclassical 5-HT receptor that we previously proposed to call 5-HT4. Here, we show that 4-amino-5-chlor-2-methoxy-benzamide derivat...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-03-01 00:00:00
abstract::The membrane-permeable, noncompetitive inositol 1,4,5-trisphosphate (IP3)-receptor inhibitor 2-aminoethoxydiphenyl borane (2-APB) has been widely used to probe for IP3-receptor involvement in calcium signaling pathways. However, a number of recent studies in different cell types revealed other sites of action of 2-APB...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.6.1304
更新日期:2003-06-01 00:00:00
abstract::The ADP-sensitive and K+ -sensitive phosphorylated forms of Na,K-ATPase (E1P and E2P, respectively) are believed to be the main phosphorylated intermediates of Na,K-ATPase. In the presence of 100 mM Na+, E2P is the major component of the phosphorylated form in all native Na,K-ATPase preparations known, including the m...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-11-01 00:00:00
abstract::Cytotoxic effects of quinones are thought to be mediated by redox cycles between quinones and quinols whereby reactive oxygen species are generated. The role of glucuronidation in preventing these toxic redox cycles was investigated by using benzo(a)pyrene-3,6-quinone and isolated rat hepatocytes or Reuber hepatoma ce...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-04-01 00:00:00
abstract::Retroviral integrases are essential for viral replication and represent an attractive chemotherapeutic target. In the current study, we demonstrated the activity of micromolar concentrations of dinucleotides against human immunodeficiency virus type 1 (HIV-1), HIV type 2 (HIV-2), simian immunodeficiency virus, and fel...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.4.567
更新日期:1997-04-01 00:00:00
abstract::Hepatocyte nuclear factor 4alpha (HNF4alpha) is a key transcription factor for the constitutive expression of cytochromes P450 (P450s) in the liver. However, human hepatoma HepG2 cells show a high level of HNF4alpha but express only marginal P450 levels. We found that the HNF4alpha-mediated P450 transcription in HepG2...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.025403
更新日期:2006-11-01 00:00:00
abstract::The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is activated by a diverse group of acidic ligands, including many peroxisome proliferator chemicals present in the environment. Janus tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) signaling is activated by multiple cyt...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.2.355
更新日期:2003-08-01 00:00:00
abstract::Rapid activation of guanine nucleotide-binding protein (G protein)-mediated signal transduction mechanisms occurs in many tissues. The human neutrophil provides a useful model for studying the mechanisms of these fast processes. Fluorescent chemotactic tetrapeptide and pentapeptide exhibit 30-50% quenching of fluoresc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-05-01 00:00:00
abstract::The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression pattern...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.115.101808
更新日期:2016-04-01 00:00:00
abstract::The bile salt export pump (BSEP/ABCB11) transports bile salts from hepatocytes into bile canaliculi. Its malfunction is associated with severe liver disease. One reason for functional impairment of BSEP is systemic administration of drugs, which as a side effect inhibit the transporter. Therefore, drug candidates are ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.117.108688
更新日期:2017-10-01 00:00:00
abstract::The beta 3-adrenergic receptor (beta 3AR) is a member of the super-family of G protein-coupled receptors that are characterized by seven putative transmembrane helices connected by hydrophilic loops. The mechanism by which the activated beta ARs transmit the signals across the plasma membrane involves the stimulation ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-09-01 00:00:00
abstract::In the human lymphocyte, desensitization of the beta-adrenergic receptor-adenylate cyclase complex is associated with sequestration of the receptor as well as a change in photolabeling of beta-receptor proteins. Thus, desensitization of the lymphocyte beta-adrenergic receptor-adenylate cyclase system is associated wit...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-11-01 00:00:00
abstract::Estrogenic and carcinogenic activity are shown to be separable properties. 2-Fluoroestradiol, a modified estrogen, did not induce renal clear-cell carcinoma in male Syrian hamsters despite its estrogenic potency, which is comparable to that of estradiol. 4-Fluoroestradiol, also a potent estrogen, did induce renal clea...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-03-01 00:00:00
abstract::We demonstrated previously that the nucleoside of fludarabine (F-ara-A), a clinically effective agent against chronic lymphocytic leukemia and low-grade lymphoma, produces synergistic cytotoxicity against cisplatin-resistant CP2.0 human colon tumor cells when administered in combination with cisplatin. The purpose of ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.5.798
更新日期:1997-11-01 00:00:00
abstract::The GABA type A receptor (GABA(A)R) is the major inhibitory receptor in the mammalian central nervous system and the target of numerous pharmaceuticals. The alpha-subunit of these pentameric Cys-loop neurotransmitter-gated ion channels contributes to the binding of both GABA and allosteric modulators such as the benzo...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.059832
更新日期:2010-07-01 00:00:00
abstract::Nicotine biotransformation affects the smoking habits of addicted individuals and therefore their health risk. Using an improved analytical method, we have discovered that the human UDP-glucuronosyltransferase (UGT) 2B10, a liver enzyme previously unknown to conjugate nicotine or exhibit considerable activity toward a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.037093
更新日期:2007-09-01 00:00:00
abstract::Multidrug resistance protein (MRP) 4 transports a variety of endogenous and xenobiotic organic anions. MRP4 is widely expressed in the body and specifically localized to the renal apical proximal tubule cell membrane, where it mediates the excretion of these compounds into urine. To characterize the MRP4 substrate-bin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.043661
更新日期:2008-10-01 00:00:00