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It is well known that information contained in a protein sequence is what allows it to fold into its three-dimensional shape, which performs a specific function. It has been possible for some time to search for proteins with similar sequences, using bioinformatics tools such as BLAST. But it is also known that proteins with similar, or even the same sequence can adopt different structures and vice-versa. With this in mind, we look to use a method called Rosetta-HMMER to perform conformationally specific sequence searches in order to exploit this property of proteins. This method involves the use of Rosetta to redesign protein structures to fit a specified α-carbon backbone, and then uses HMMER to generate a sequence profile. This profile can then be used to query for sequences able to adopt the specified backbone structure. These collected sequences can then be aligned for the purpose of performing statistical coupling analysis. We have used this Rosetta-HMMER method in conjunction with available structures of the α7 acetylcholine receptor to show that distinct sequence profiles generated from different conformations of the same protein are capable of retrieving unique sets of natural sequences when used as a query. We have also shown that when these unique sets of natural sequences are used to perform statistical coupling analysis, different residues are identified as statistically coupled, potentially generating insight into residues that have more potential importance for one backbone conformation over another.

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Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

The mechanism of action of insulin and epidermal growth factor was studied by genetic and biochemical means. Particular emphasis was placed on the ability of these factors to induce DNA synthesis and the relationship of endocytosis to that ability. Insulin was crosslinked to the active fragment A of diphtheria toxin. This conjugate specifically killed cultured mouse cells through an insulin receptor-mediated process. The conjugate was used to select genetic variants resistant to its cytotoxic effect. Six resistant variants were isolated, 2 of which retained very low insulin receptor activity. When these two variants were further analyzed both displayed altered cell shape and growth properties. The CI-3 variant also was shown to have a deficient lysosomal system and failed to efficiently degrade epidermal growth factor. This variant was, however, fully responsive to the mitogenic action of EGF. This suggested that lysosomal processing is unimportant in the production of a mitogenic stimulus by EGF. EGF was found to be endocytosed by fibroblasts through 2 separate pathways. One pathway involves an unidentified organelle and correlated with increased degradation of the ligand. The other pathway involves a Golgi-like component and is correlated with a lack of degradation and uptake into a dense, non-lysosomal organelle. Uptake of EGF into this non-lysosomal component, which we named mitosomes, correlated with the ability of EGF to induce DNA synthesis. From these results, a model was constructed for the coupling of endocytosis, uptake into mitosomes and the stimulation of DNA synthesis.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Šárka Tomanová Supervisors: Prof. PharmDr. Martin Doležal, Ph.D., Prof. Dr. Christa Elisabeth Müller Title of diploma thesis: Development of a reliable test system for purinergic P2X3 receptors Purinergic P2X3 receptor is a ligand-gated ionotropic channel that occurs in all mammalian tissues. The highest occurrence has been observed in central and peripheral nervous system and smooth muscles, where P2X3 receptors participate in pathological disorders such as visceral and neurophatic pain, inflammatory reactions and psychiatric disorders. Compounds capable of blocking P2X3 receptor activity could be therefore used as potential drugs for treatment of these states. P2X3 receptor belongs to fast- desensitizing ionotropic channels, which makes the measurement of its activity very difficult. It was described that one point S15V mutation, in which the amino acid serine in a position 15 is replaced by amino acid valine, slows down the desensitization rate and the signal becomes easily measurable. This simple mutation may be used as an effective tool for characterization of insufficiently explored P2X3 receptor. The P2X3 S15V receptor DNA was inserted into retrovirus and,...

Wong Yuk-Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1992. / Includes bibliographical references (leaves 132-152). / abstract --- p.1 / ACKNOWLEDGEMENT --- p.4 / content --- p.6 / Chapter I. --- INTRODUCTION --- p.8 / Chapter II. --- literature reviews --- p.11 / Chapter 1. --- Menstrual cycle --- p.11 / Chapter 2. --- oestrogen receptor and progesterone receptor --- p.18 / Chapter 3. --- Monoclonal antibody assays for the study of oestrogen and progesterone receptors --- p.30 / Chapter III. --- materials and methods --- p.35 / Chapter 1. --- study population --- p.35 / Chapter 2. --- sample collection and analysis JO --- p.36 / Chapter 3. --- Histological dating of endometrial biopsies --- p.37 / Chapter 4. --- Determination of oestrogen and progesterone receptors using immunocytochemical assay --- p.38 / Chapter 5. --- Determination of oestrogen and progesterone receptors using enzyme immunoassay --- p.52 / Chapter 6. --- Determination of serum oestradiol and progesterone --- p.66 / Chapter 7. --- Data handling and statistical analysis --- p.76 / Chapter IV. --- results --- p.77 / Chapter 1. --- Study population --- p.77 / Chapter 2. --- Histological dating of endometrial biopsies --- p.77 / Chapter 3. --- oestrogen and progesterone receptors in frozen section of endometrium in menstrual cycle --- p.80 / Chapter 4. --- oestrogen and progesterone receptors in paraffin section of endometrium in menstrual cycle --- p.95 / Chapter 5. --- Oestrogen and progesterone receptors in endometrium in menstrual cycle determined by enzyme immunoassay --- p.113 / Chapter 6. --- Serum oestradiol and progesterone --- p.116 / Chapter V. --- DISCUSSIONS --- p.120 / Chapter 1. --- oestrogen and progesterone receptors in frozen section of endometrium in menstrual cycle --- p.121 / Chapter 2. --- Oestrogen and progesterone receptors in paraffin section of endometrium in menstrual cycle --- p.124 / Chapter 3. --- oestrogen and progesterone receptors in endometrium in menstrual cycle determined by enzyme immunoassay --- p.127 / Chapter 4. --- Potential application of oestrogen and progesterone receptors in endometrium in menstrual cycle --- p.129 / REFERENCE --- p.132