Identification of a new class of inhibitors of the voltage-gated potassium channel, Kv1.3, with immunosuppressant properties.

Abstract:

:The voltage-gated potassium channel, K(v)1.3, is a novel target for development of immunosuppressants. Using a functional (86)Rb(+) efflux assay, a new class of high-affinity K(v)1.3 inhibitors has been identified. The initial active in this series, 4-phenyl-4-[3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl]cyclohexanone (PAC), which is representative of a disubstituted cyclohexyl (DSC) template, displays a K(i) of ca. 300 nM and a Hill coefficient near 2 in the flux assay and in voltage clamp recordings of K(v)1.3 channels in human T-lymphocytes. PAC displays excellent specificity as it only blocks members of the K(v)1 family of potassium channels but does not affect many other types of ion channels, receptors, or enzyme systems. Block of K(v)1.3 by DSC analogues occurs with a well-defined structure-activity relationship. Substitution at the C-1 ketone of PAC generates trans (down) and cis (up) isomer pairs. Whereas many DSC derivatives do not display selectivity in their interaction with different K(v)1.x channels, trans DSC derivatives distinguish between K(v)1.x channels based on their rates of C-type inactivation. DSC analogues reversibly inhibit the Ca(2+)-dependent pathway of T cell activation in in vitro assays. Together, these data suggest that DSC derivatives represent a new class of immunosuppressant agents and that specific interactions of trans DSC analogues with channel conformations related to C-type inactivation may permit development of selective K(v)1.3 channel inhibitors useful for the safe treatment of autoimmune diseases.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Schmalhofer WA,Bao J,McManus OB,Green B,Matyskiela M,Wunderler D,Bugianesi RM,Felix JP,Hanner M,Linde-Arias AR,Ponte CG,Velasco L,Koo G,Staruch MJ,Miao S,Parsons WH,Rupprecht K,Slaughter RS,Kaczorowski GJ,Garcia ML

doi

10.1021/bi025722c

subject

Has Abstract

pub_date

2002-06-18 00:00:00

pages

7781-94

issue

24

eissn

0006-2960

issn

1520-4995

pii

bi025722c

journal_volume

41

pub_type

杂志文章
  • Electrical potential of transfer RNAs: codon-anticodon recognition.

    abstract::Calculations of the electrostatic potentials were made around yeast elongator phenylalanine, aspartate tRNAs, and yeast initiator methionine tRNA in aqueous solution at physiological ionic strength. The calculations were carried out with a finite difference algorithm for solving the nonlinear Poisson-Boltzmann equatio...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00454a006

    authors: Sharp KA,Honig B,Harvey SC

    更新日期:1990-01-16 00:00:00

  • Cobalt-cytochrome c. I. Preparation, properties, and enzymic activity.

    abstract::An improved procedure for the preparation of cobalt-cytochrome c has been developed. Various factors influencing the cobalt insertion process are discussed. The optical spectra of cobalt-cytochrome c suggest a six-coordinated species. The spectral shifts occurring with oxidation-reduction are compared with those obser...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00687a003

    authors: Dickinson LC,Chien JC

    更新日期:1975-08-12 00:00:00

  • Nucleotide- and substrate-induced conformational transitions in the CBS domain-containing pyrophosphatase of Moorella thermoacetica.

    abstract::In contrast to all other known pyrophosphatases, Moorella thermoacetica pyrophosphatase (mtCBS-PPase) contains nucleotide-binding CBS domains and is thus strongly regulated by adenine nucleotides. Stopped-flow measurements using a fluorescent AMP analogue, 2'(3')-O-(N-methylanthranoyl)-AMP (Mant-AMP), reveal that nucl...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9019737

    authors: Jämsen J,Baykov AA,Lahti R

    更新日期:2010-02-09 00:00:00

  • Potentiation of progesterone receptor-mediated transcription by the immunosuppressant FK506.

    abstract::The nontransformed steroid receptors contain several non-steroid binding proteins, such as hsp90, hsp70, and p59. Recently, we and others have shown that p59 (FKBP59) is an immunophilin which binds two potent immunosuppressants, FK506 and rapamycin. This raises the possibility that FK506 or rapamycin may modify the fu...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00201a014

    authors: Tai PK,Albers MW,McDonnell DP,Chang H,Schreiber SL,Faber LE

    更新日期:1994-09-06 00:00:00

  • Carbon monoxide dehydrogenase from Clostridium thermoaceticum: quaternary structure, stoichiometry of its SDS-induced dissociation, and characterization of the faster-migrating form.

    abstract::The molecular mass (M(r)) of the nickel- and iron-sulfur-containing enzyme CO dehydrogenase from Clostridium thermoaceticum was determined by sedimentation equilibrium ultracentrifugation to be 300,000 +/- 30,000 Da. Since the enzyme is known to contain equal numbers of two types of subunits (M(r) = 82,000 Da for alph...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9511853

    authors: Xia J,Sinclair JF,Baldwin TO,Lindahl PA

    更新日期:1996-02-13 00:00:00

  • Reconsidering the mechanism of polyglutamine peptide aggregation.

    abstract::There are at least nine neurodegenerative diseases associated with proteins that contain an unusually expanded polyglutamine domain, the best known of which is Huntington's disease. In all of these diseases, the mutant protein aggregates into neuronal inclusions; it is generally, although not universally, believed tha...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi700806c

    authors: Lee CC,Walters RH,Murphy RM

    更新日期:2007-11-06 00:00:00

  • Evidence for a slow tertiary relaxation in the reaction of tert-butyl isocyanide with horseradish peroxidase.

    abstract::The kinetics of tert-butyl isocyanide binding to the heme protein horseradish peroxidase (HRP) at 22 degrees C was examined on all time scales, from minutes to picoseconds, in aqueous borate buffer at pH 9.08. Unlike myoglobin (Mb) or hemoglobin, HRP shows two bimolecular ligand binding processes. For comparison, bind...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9518149

    authors: Bandyopadhyay D,Walda KN,Grogan TM,Magde D,Traylor TG,Sharma VS

    更新日期:1996-02-06 00:00:00

  • Spatial proximity of the glycine-rich loop and the SH2 thiol in myosin subfragment 1.

    abstract::Subfragment 1 (S1) prepared from rabbit skeletal muscle myosin was digested with trypsin to cleave the 95K heavy chain into three pieces, i.e., the 23K, 50K, and 20K fragments. The trypsin-treated S1 was then cross-linked with p-nitrophenyl iodoacetate. The cross-linker bridged one of the reactive thiols (SH2) in the ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00408a045

    authors: Sutoh K,Hiratsuka T

    更新日期:1988-04-19 00:00:00

  • Mechanism of the orotidine 5'-monophosphate decarboxylase-catalyzed reaction: importance of residues in the orotate binding site.

    abstract::The reaction catalyzed by orotidine 5'-monophosphate decarboxylase (OMPDC) is accompanied by exceptional values for rate enhancement (k(cat)/k(non) = 7.1 × 10(16)) and catalytic proficiency [(k(cat)/K(M))/k(non) = 4.8 × 10(22) M(-1)]. Although a stabilized vinyl carbanion/carbene intermediate is located on the reactio...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi2012355

    authors: Iiams V,Desai BJ,Fedorov AA,Fedorov EV,Almo SC,Gerlt JA

    更新日期:2011-10-04 00:00:00

  • Decrypting the structural, dynamic, and energetic basis of a monomeric kinesin interacting with a tubulin dimer in three ATPase states by all-atom molecular dynamics simulation.

    abstract::We have employed molecular dynamics (MD) simulation to investigate, with atomic details, the structural dynamics and energetics of three major ATPase states (ADP, APO, and ATP state) of a human kinesin-1 monomer in complex with a tubulin dimer. Starting from a recently solved crystal structure of ATP-like kinesin-tubu...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi501056h

    authors: Chakraborty S,Zheng W

    更新日期:2015-01-27 00:00:00

  • Proton NMR and structural features of a 24-nucleotide RNA hairpin.

    abstract::The three-dimensional conformation of a 24-nucleotide variant of the RNA binding sequence for the coat protein of bacteriophage R17 has been analyzed using NMR, molecular dynamics, and energy minimization. The imino proton spectrum is consistent with base pairing requirements for coat protein binding known from bioche...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00019a030

    authors: Borer PN,Lin Y,Wang S,Roggenbuck MW,Gott JM,Uhlenbeck OC,Pelczer I

    更新日期:1995-05-16 00:00:00

  • Room temperature trapping of rhodopsin photointermediates.

    abstract::By suspending bovine rhodopsin in trehalose-water glass films, it is possible to trap photostates in the light-activation process. Because of the unusually high vitrification temperature of trehalose-water mixtures, this trapping can be accomplished at room temperature. This allows for a facile investigation of the sp...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00181a004

    authors: Sikora S,Little AS,Dewey TG

    更新日期:1994-04-19 00:00:00

  • Importance of asparagine-61 and asparagine-109 to the angiogenic activity of human angiogenin.

    abstract::Two distinct regions of angiogenin are critical for angiogenic activity: a catalytic site capable of cleaving RNA and a noncatalytic site, encompassing residues 60-68, which may bind to an endothelial cell-surface receptor [Hallahan, T. W., Shapiro, R., & Vallee, B. L. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 2222-222...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00149a036

    authors: Hallahan TW,Shapiro R,Strydom DJ,Vallee BL

    更新日期:1992-09-01 00:00:00

  • Activating anions that replace Cl- in the O2-evolving complex of photosystem II slow the kinetics of the terminal step in water oxidation and destabilize the S2 and S3 states.

    abstract::Photosystem II, the multisubunit protein complex that oxidizes water to O2, requires the inorganic cofactors Ca2+ and Cl- to exhibit optimal activity. Chloride can be replaced functionally by a small number of anionic cofactors (Br-, NO3-, NO2-, I-), but among these anions, only Br- is capable of restoring rates of ox...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi982295n

    authors: Wincencjusz H,Yocum CF,van Gorkom HJ

    更新日期:1999-03-23 00:00:00

  • 3 Beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase from bovine adrenals: mechanism of inhibition by 3-oxo-4-aza steroids and kinetic mechanism of the dehydrogenase.

    abstract::Several 3-oxo-4-aza steroids (1) have been identified as inhibitors of the 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase catalyzed conversion of pregnenolone to progesterone. By kinetically decoupling the two enzyme activities isolated from bovine adrenal cortex, it has been demonstrate...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00427a021

    authors: Brandt M,Levy MA

    更新日期:1989-01-10 00:00:00

  • Isolation and characterization of a dog serum lipoprotein having apolipoprotein A-I as its predominant protein constituent.

    abstract::The serum high density lipoproteins (HDL) of normolipemic dogs (beagles) were isolated in the density range of p 1.063 to 1.21 g/ml, and characterized in terms of composition and physical properties (flotation and diffusion coefficients, partial specific volume, molecular weight, electrophoretic mobility, ultraviolet ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00654a022

    authors: Edelstein C,Lewis LL,Shainoff JR,Naito H,Scanu AM

    更新日期:1976-05-04 00:00:00

  • Interaction of tetrahydrofolate and other folate derivatives with bacterial sarcosine oxidase.

    abstract::Sarcosine oxidase from Corynebacterium sp. P-1 binds 2 mol of tetrahydrofolate/mol of enzyme (KD = 8.8 microM). The same stoichiometry is observed with tetrahydropteroyltetraglutamate (KD = 15.4 microM). Binding is also observed with pteroyltetraglutamate and with 5-formyltetrahydrofolate. In the case of the pteroylmo...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00397a029

    authors: Kvalnes-Krick K,Jorns MS

    更新日期:1987-11-17 00:00:00

  • Assignment of spectral substructures to pigment-binding sites in higher plant light-harvesting complex LHC-II.

    abstract::The trimeric main light-harvesting complex (LHC-II) is the only antenna complex of higher plants of which a high-resolution 3D structure has been obtained (Kühlbrandt, W., Wang, D., and Fujiyoshi, Y. (1994) Nature 367, 614-621) and which can be refolded in vitro from its components. Four different recombinant forms of...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi015875k

    authors: Rogl H,Schödel R,Lokstein H,Kühlbrandt W,Schubert A

    更新日期:2002-02-19 00:00:00

  • Product Release Mechanism Associated with Structural Changes in Monomeric l-Threonine 3-Dehydrogenase.

    abstract::A short chain dehydrogenase like l-threonine 3-dehydrogenase (SDR-TDH) from metagenome data (mtTDH) was identified by database mining. Its enzymatic properties suggested that mtTDH has unique characteristics relative to other SDR-TDHs, including two mesophilic and thermophilic SDR-TDHs identified in this study. The ac...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/acs.biochem.7b00832

    authors: Motoyama T,Nakano S,Yamamoto Y,Tokiwa H,Asano Y,Ito S

    更新日期:2017-10-31 00:00:00

  • Structures of phage-display peptides that bind to the malarial surface protein, apical membrane antigen 1, and block erythrocyte invasion.

    abstract::Apical membrane antigen 1 (AMA1) of the human malaria parasite Plasmodium falciparum is synthesized by schizont stage parasites and has been implicated in merozoite invasion of host erythrocytes. Phage-display techniques have recently been used to identify two 15-residue peptides, F1 and F2, which bind specifically to...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi034376b

    authors: Keizer DW,Miles LA,Li F,Nair M,Anders RF,Coley AM,Foley M,Norton RS

    更新日期:2003-08-26 00:00:00

  • Tandem affinity purification in transgenic mouse embryonic stem cells identifies DDOST as a novel PPP1CC2 interacting protein.

    abstract::Members of the PP1 family of protein phosphatases achieve functional diversity through numerous and varied protein-protein interactions. In mammals, there are four PP1 isoforms, the ubiquitously expressed PPP1CA, PPP1CB, and PPP1CC1, and the testis specific splice isoform PPP1CC2. When the mouse Ppp1cc gene is deleted...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi3010158

    authors: MacLeod G,Varmuza S

    更新日期:2012-12-04 00:00:00

  • Presence of divalent cation is not mandatory for the formation of intramolecular purine-motif triplex containing human c-jun protooncogene target.

    abstract::Modulation of endogenous gene function, through sequence-specific recognition of double helical DNA via oligonucleotide-directed triplex formation, is a promising approach. Compared to the formation of pyrimidine motif triplexes, which require relatively low pH, purine motif appears to be the most gifted for their sta...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi1012589

    authors: Kaushik S,Kaushik M,Svinarchuk F,Malvy C,Fermandjian S,Kukreti S

    更新日期:2011-05-17 00:00:00

  • Binding of protein synthesis initiation factor 4E to oligoribonucleotides: effects of cap accessibility and secondary structure.

    abstract::The binding of rabbit globin mRNA to the 25-kDa cap binding protein eIF-4E from human erythrocytes was found to be 5.3-fold stronger than the binding of the cap analogue m7GpppG to eIF-4E [Gross et al. (1990) Biochemistry 29, 5008-5012]. In order to investigate whether this effect is due to the longer sequence of nucl...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00120a020

    authors: Carberry SE,Friedland DE,Rhoads RE,Goss DJ

    更新日期:1992-02-11 00:00:00

  • Functional groups at the catalytic site of BF1 adenosinetriphosphatase from Escherichia coli.

    abstract::The rates of inactivation of BF1 adenosinetriphosphatase (BF1-ATPase) from Escherichia coli by 7-chloro-4-nitro-2,1,3-benzoxadiazole, 1-fluoro-2,4-dinitrobenzene, 2,4,6-trinitrobenzenesulfonate, phenylglyoxal, and N,N'-dicyclohexylcarbodiimide have been measured in the presence and absence of various concentrations of...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00531a011

    authors: Ting LP,Wang JH

    更新日期:1982-01-19 00:00:00

  • Evidence that the principal CoII-binding site in human serum albumin is not at the N-terminus: implication on the albumin cobalt binding test for detecting myocardial ischemia.

    abstract::Human serum albumin (HSA) is the most abundant protein in the blood plasma and is involved in the transport of metal ions. Four metal-binding sites with different specificities have been described in HSA: (i) the N-terminal site provided by Asp1, Ala2, and His3, (ii) the site at the reduced Cys34, (iii) site A, includ...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi061783p

    authors: Mothes E,Faller P

    更新日期:2007-02-27 00:00:00

  • Evidence for distinct DNA binding forms of the erythroid-specific transcription factor NF-E2.

    abstract::The transcriptional activity of the beta-globin genes is regulated by a complex genetic element, the locus control region (LCR), at the 5'-end of the beta-globin locus. Tandem binding sites for the erythroid-specific transcription factor NF-E2 are important for the transcriptional activation function of the LCR. We di...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00050a015

    authors: Lam LT,Bresnick EH

    更新日期:1995-12-19 00:00:00

  • Activation of cGMP phosphodiesterase in retinal rods: mechanism of interaction with the GTP-binding protein (transducin).

    abstract::The mechanism of activation of cGMP phosphodiesterase by the GTP-binding protein in the disc membrane of retinal rods has been investigated by measuring the light-induced phosphodiesterase activity in reconstituted systems where the concentration of either the GTP-binding protein or the phosphodiesterase is varied. Th...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00444a040

    authors: Bennett N,Clerc A

    更新日期:1989-09-05 00:00:00

  • Thioredoxin reductase-thioredoxin fusion enzyme from Mycobacterium leprae: comparison with the separately expressed thioredoxin reductase.

    abstract::Thioredoxin reductase (TrxR) catalyzes the reduction of thioredoxin (Trx) by NADPH. A unique gene organization of TrxR and Trx has been found in Mycobacterium leprae, where TrxR and Trx are encoded by a single gene and, therefore, are expressed as a fusion protein (MlTrxR-Trx). This fusion enzyme is able to catalyze t...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi980754e

    authors: Wang PF,Marcinkeviciene J,Williams CH Jr,Blanchard JS

    更新日期:1998-11-17 00:00:00

  • Requirement of histidine 217 for ubiquinone reductase activity (Qi site) in the cytochrome bc1 complex.

    abstract::Folding models suggest that the highly conserved histidine 217 of the cytochrome b subunit from the cytochrome bc1 complex is close to the quinone reductase (Qi) site. This histidine (bH217) in the cytochrome b polypeptide of the photosynthetic bacterium Rhodobacter capsulatus has been replaced with three other residu...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi00169a014

    authors: Gray KA,Dutton PL,Daldal F

    更新日期:1994-01-25 00:00:00

  • The ice-binding site of sea raven antifreeze protein is distinct from the carbohydrate-binding site of the homologous C-type lectin.

    abstract::Antifreeze proteins lower the freezing point of their solution by binding to ice and inhibiting its growth. One of several structurally different antifreeze proteins in fishes (type II) is homologous to the carbohydrate-recognition domain of Ca2+-dependent lectins and adopts the same three-dimensional fold. Type II an...

    journal_title:Biochemistry

    pub_type: 杂志文章

    doi:10.1021/bi9820513

    authors: Loewen MC,Gronwald W,Sönnichsen FD,Sykes BD,Davies PL

    更新日期:1998-12-22 00:00:00