more information
Search within Results:

Select All    Deselect All
 |   | 
Details
   print
  Records Links
Author (up) Alonso, A.; Almendral, M.J.; Curto, Y.; Criado, J.J.; Rodriguez, E.; Manzano, J.L. file  url
openurl 
  Title Determination of the DNA-binding characteristics of ethidium bromide, proflavine, and cisplatin by flow injection analysis: usefulness in studies on antitumor drugs Type Journal Article
  Year 2006 Publication Analytical Biochemistry Abbreviated Journal Anal Biochem  
  Volume 355 Issue 2 Pages 157-164  
  Keywords Antineoplastic Agents--chemistry, metabolism; Binding Sites; Cisplatin--chemistry, metabolism; DNA--chemistry, metabolism; Ethidium--chemistry, metabolism; Flow Injection Analysis--methods; Fluorescent Dyes; Kinetics; Nucleic Acid Conformation; Proflavine--chemistry, metabolism; Spectrometry, Fluorescence  
  Abstract Flow injection analysis was used to study the reactions occurring between DNA and certain compounds that bind to its double helix, deforming this and even breaking it, such that some of them (e.g., cisplatin) are endowed with antitumoral activity. Use of this technique in the merging zones and stopped-flow modes afforded data on the binding parameters and the kinetic characteristics of the process. The first compound studied was ethidium bromide (EtdBr), used as a fluorescent marker because its fluorescence is enhanced when it binds to DNA. The DNA-EtdBr binding parameters, the apparent intrinsic binding constant (0.31+/-0.02 microM(-1)), and the maximum number of binding sites per nucleotide (0.327+/-0.009) were determined. The modification introduced in these parameters by the presence of proflavine (Prf), a classic competitive inhibitor of the binding of EtdBr to the DNA double helix, was also studied, determining the value of the intrinsic binding constant of Prf (K(Prf) = 0.119+/-9x10(-3) microM(-1)). Finally, we determined the binding parameters between DNA and EtdBr in the presence of the antitumor agent cisplatin, a noncompetitive inhibitor of such binding. This provided information about the binding mechanism as well as the duration and activity of the binding of the compound in its pharmacological use.  
  Call Number Serial 363  
Permanent link to this record
 

 
Author (up) Baylis, H.A.; Furuichi, T.; Yoshikawa, F.; Mikoshiba, K.; Sattelle, D.B. file  url
openurl 
  Title Inositol 1,4,5-trisphosphate receptors are strongly expressed in the nervous system, pharynx, intestine, gonad and excretory cell of Caenorhabditis elegans and are encoded by a single gene (itr-1) Type Journal Article
  Year 1999 Publication Journal of Molecular Biology Abbreviated Journal J Mol Biol  
  Volume 294 Issue 2 Pages 467-476  
  Keywords Amino Acid Sequence; Animals; Animals, Genetically Modified; Binding Sites; Caenorhabditis elegans/*genetics; Calcium Channels/*genetics/*metabolism; Cell Membrane/genetics/metabolism; Conserved Sequence; Gene Expression Profiling; Gonads/metabolism; Helminth Proteins/*genetics/*metabolism; Inositol 1,4,5-Trisphosphate Receptors; Intestines/metabolism; Molecular Sequence Data; Nervous System/metabolism; Pharynx/metabolism; RNA, Messenger; Receptors, Cytoplasmic and Nuclear/*genetics/*metabolism; Rectum/cytology/metabolism  
  Abstract Inositol 1,4,5-trisphosphate (InsP3) activates receptors (InsP3Rs) that mediate intracellular Ca(2+ )release, thereby modulating intracellular calcium signals and regulating important aspects of cellular physiology and gene expression. To further our understanding of InsP3Rs we have characterised InsP3Rs and the InsP3R gene, itr-1, from the model organism Caenorhabditis elegans. cDNAs encoding InsP3Rs were cloned enabling us to: (a) identify three putative transcription start sites that result in alternative mRNA 5' ends: (b) detect alternative splicing at three sites and: (c) determine the full genomic organisation of the itr-1 gene. The InsP3R protein (ITR-1) is approximately 42 % identical with known InsP3Rs and possesses conserved structural features. When the putative InsP3 binding domain was expressed in Escherichia coli, specific binding of InsP3 was detected. Using antibodies against ITR-1 we detected a protein of 220 kDa in C. elegans membranes. These antibodies and itr-1::GFP (green fluorescent protein) reporter constructs were used to determine the expression pattern of itr-1 in C. elegans. Strong expression was observed in the intestine, pharynx, nerve ring, excretory cell and gonad. These results demonstrate the high degree of structural and functional conservation of InsP3Rs from nematodes to mammals and the utility of C. elegans as a system for studies on InsP3R mediated signalling.  
  Call Number Serial 309  
Permanent link to this record
 

 
Author (up) Bertrand, D.; Gopalakrishnan, M. file  url
openurl 
  Title Allosteric modulation of nicotinic acetylcholine receptors Type Journal Article
  Year 2007 Publication Biochemical Pharmacology Abbreviated Journal Biochem Pharmacol  
  Volume 74 Issue 8 Pages 1155-1163  
  Keywords Allosteric Regulation; Animals; Binding Sites; Dose-Response Relationship, Drug; Humans; Receptors, Nicotinic/*chemistry/*drug effects; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract Allosteric modulation refers to the concept that proteins could exist in multiple conformational states and that binding of allosteric ligands alters the energy barriers or “isomerization coefficients” between various states. In the context of ligand gated ion channels such as nicotinic acetylcholine receptors (nAChRs), it implies that endogenous ligand acetylcholine binds at the orthosteric site, and that molecules that bind elsewhere on the nAChR subunit(s) acts via allosteric interactions. For example, studies with the homomeric alpha7 nAChRs indicate that such ligand interactions can be well described by an allosteric model, and that positive allosteric effectors can affect energy transitions by (i) predominantly affecting the peak current response (Type I profile) or, (ii) both peak current responses and time course of agonist-evoked response (Type II profile). The recent discovery of chemically heterogeneous group of molecules capable of differentially modifying nAChR properties without interacting at the ligand binding site illustrates the adequacy of the allosteric model to predict functional consequences. In this review, we outline general principles of the allosteric concept and summarize the profiles of novel compounds that are emerging as allosteric modulators at the alpha7 and alpha4beta2 nAChR subtypes.  
  Call Number Serial 1877  
Permanent link to this record
 

 
Author (up) Bertrand, D.; Gopalakrishnan, M. file  url
openurl 
  Title Allosteric modulation of nicotinic acetylcholine receptors Type Journal Article
  Year 2007 Publication Biochemical Pharmacology Abbreviated Journal Biochem Pharmacol  
  Volume 74 Issue 8 Pages 1155-1163  
  Keywords Allosteric Regulation; Animals; Binding Sites; Dose-Response Relationship, Drug; Humans; Receptors, Nicotinic/*chemistry/*drug effects; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract Allosteric modulation refers to the concept that proteins could exist in multiple conformational states and that binding of allosteric ligands alters the energy barriers or “isomerization coefficients” between various states. In the context of ligand gated ion channels such as nicotinic acetylcholine receptors (nAChRs), it implies that endogenous ligand acetylcholine binds at the orthosteric site, and that molecules that bind elsewhere on the nAChR subunit(s) acts via allosteric interactions. For example, studies with the homomeric alpha7 nAChRs indicate that such ligand interactions can be well described by an allosteric model, and that positive allosteric effectors can affect energy transitions by (i) predominantly affecting the peak current response (Type I profile) or, (ii) both peak current responses and time course of agonist-evoked response (Type II profile). The recent discovery of chemically heterogeneous group of molecules capable of differentially modifying nAChR properties without interacting at the ligand binding site illustrates the adequacy of the allosteric model to predict functional consequences. In this review, we outline general principles of the allosteric concept and summarize the profiles of novel compounds that are emerging as allosteric modulators at the alpha7 and alpha4beta2 nAChR subtypes.  
  Call Number Serial 1887  
Permanent link to this record
 

 
Author (up) Giles, G.I.; Sharma, R.P. file  url
openurl 
  Title Topoisomerase enzymes as therapeutic targets for cancer chemotherapy Type Journal Article
  Year 2005 Publication Medicinal Chemistry (Shariqah (United Arab Emirates)) Abbreviated Journal Med Chem  
  Volume 1 Issue 4 Pages 383-394  
  Keywords Antineoplastic Agents/pharmacology/*therapeutic use; Binding Sites; *Drug Delivery Systems; *Drug Therapy; Enzyme Inhibitors/pharmacology/therapeutic use; Humans; Models, Molecular; Neoplasms/*drug therapy; *Topoisomerase I Inhibitors; *Topoisomerase II Inhibitors  
  Abstract The topoisomerase enzymes are essential for DNA metabolism, where they act to adjust the number of supercoils in DNA, a key requirement in the cellular processes of transcription and replication. Their enzymatic mechanism creates transient nicks (type I) or breaks (type II) in the double stranded DNA polymer, allowing DNA to be converted between topological isomers. Humans possess both types of topoisomerase enzymes, however the two types utilize very different enzymatic mechanisms. Both type I and type II topoisomerases have been identified as clinically important targets for cancer chemotherapy and their inhibitors are central components in many therapeutic regimes. Over the course of the last 30 years inhibitors with extensive structural diversity have been developed through a combination of drug screening and rational design programs. Simultaneously much emphasis has been placed upon establishing the mechanisms of action of both classes of topoisomerase enzyme. Crucial structural insights have come from the crystal structure of topoisomerase I, while modelling comparisons are beginning to map out a possible framework for topoisomerase II action. This review discusses these recent advances in the fields of enzyme mechanism and inhibitor design. We also address the development of drug resistance and dose-limiting side effects as well as cover alternative methods in drug delivery.  
  Call Number Serial 200  
Permanent link to this record
Select All    Deselect All
 |   | 
Details
   print

Save Citations: