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An algorithm has been devised for the automatic design of peptide turn mimetics, particularly applicable to peptide-activated GPCRs. The method is based on flexible alignments using a new design paradigm and scoring system that aims to reduce the molecular weight of the compound and preferentially lead to drug like molecules. The process can be applied either as a de novo design or a virtual screening tool. Its use has been demonstrated by the design of novel double digit nanomolar ligands for the melanocortin 4 receptor (MC4). The method is, in principle, applicable to any type of receptor, including orphan receptors. 相似文献
14.
A set of TROSY-HNCO (tHNCO)-based 3D experiments is presented for measuring 15N relaxation parameters in large, membrane-associated proteins, characterized by slow tumbling times and significant spectral
overlap. Measurement of backbone 15N R
1, R
1ρ, 15N–{1H} NOE, and 15N CSA/dipolar cross correlation is demonstrated and applied to study the dynamic behavior of the homotetrameric KcsA potassium
channel in SDS micelles under conditions where this channel is in the closed state. The micelle-encapsulated transmembrane
domain, KcsATM, exhibits a high degree of order, tumbling as an oblate ellipsoid with a global rotational correlation time, τc = 38 ± 2.5 ns, at 50 °C and a diffusion anisotropy, , corresponding to an aspect ratio a/b ≥ 1.4. The N- and C-terminal intracellular segments of KcsA exhibit considerable internal dynamics (S
2 values in the 0.2–0.45 range), but are distinctly more ordered than what has been observed for unstructured random coils.
Relaxation behavior in these domains confirms the position of the C-terminal helix, and indicates that in SDS micelles, this
amphiphilic helix does not associate into a stable homotetrameric helical bundle. The relaxation data indicate the absence
of elevated backbone dynamics on the ps–ns time scale for the 5-residue selectivity filter, which selects K+ ions to enter the channel.
Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at .
An erratum to this article can be found at 相似文献
15.
A constant-time, Carr-Purcell-Meiboom-Gill (CPMG) transverse relaxation, R(2), dispersion experiment for carbonyl carbons was designed and executed to detect micros-ms time-scale dynamics of protein backbone carbonyl sites. Because of the large (ca. 55 Hz) C(alpha)-C' J-coupling, the carbonyl signal intensity is strongly modulated as the spacing between CPMG pulses is varied, in uniformly (13)C enriched proteins, unless care is taken to minimize the perturbation of the C(alpha) magnetization by the CPMG pulses. CPMG pulse trains consisting of either a band-selective pulse, such as RE-BURP, or rectangular (with an excitation null in the C(alpha) region of the spectrum) pulses were employed in order to minimize C' signal modulation by C(alpha)-C' J-coupling. The performance of these types of CPMG refocusing pulses was assessed by computer simulation, and by comparing dispersion profiles measured for (1) uniformly [(13)C,(15)N, (2)H] ((2)H at non-labile hydrogen sites) labeled, and (2) uniformly (15)N/selectively-(13)C' labeled samples of HIV-1 protease bound to a potent inhibitor, DMP323. In addition, because the uniformly (13)C/(15)N/(2)H labeled sample was well suited to measure (15)N and (1)H R(2) dispersion as well as (13)C' dispersion, conformational exchange in the inter subunit beta-sheet hydrogen-bond network of the inhibitor-bound protease was elucidated using relaxation dispersion data of all three types of nuclei. 相似文献
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Clonal characterization of fibroblasts in the superficial layer of the adult human dermis 总被引:4,自引:0,他引:4
The dermis of adult human skin contains a physiologically heterogeneous population of fibroblasts that interact to produce
its unique architecture and that participate in inflammatory and wound repair functions in vivo. This heterogeneity has been
well documented for fibroblasts located in the superficial papillary dermis and the deep reticular dermis. However, the existence
of diverse fibroblast subpopulations within a given region of the dermis has not been explored. In this study, fibroblast
cultures have been established from the superficial dermis following enzymatic dissociation of the tissue. These fibroblasts
have been cloned by limiting dilution and initially selected on the basis of morphology and proliferation kinetics. Fibroblasts
in some of the clones selected for study express α-smooth muscle actin, a myofibroblast characteristic. Significant differences
for fibroblast clones obtained from the same piece of skin have been observed with regard to their rate of collagen lattice
contraction, their ability to organize a fibronectin matrix, their release of specific growth factors/cytokines into culture
medium, and their response to interleukin-1α. These differences in both morphological and physiological characteristics indicate
that the superficial papillary dermis contains a heterogeneous population of fibroblasts. This heterogeneity might indicate
that diverse subpopulations of fibroblasts are required to interact in both homeostatic and pathological situations in skin.
We thank L’Oréal Life Sciences for providing funding for these studies. 相似文献
18.
Differential effects of losartan and candesartan on vasoconstrictor responses in the rat 总被引:1,自引:0,他引:1
Nossaman BD Baber SR Nazim MM Detrolio JD Kadowitz PJ 《Canadian journal of physiology and pharmacology》2007,85(3-4):360-371
Losartan has been reported to have inhibitory effects on thromboxane (TP) receptor-mediated responses. In the present study, the effects of 2 nonpeptide angiotensin II (AT1) receptor antagonists, losartan and candesartan, on responses to angiotensin II, the thromboxane A2 mimic, U46619, and norepinephrine were investigated and compared in the pulmonary and systemic vascular beds of the intact-chest rat. In this study, intravenous injections of angiotensin II, U46619, and norepinephrine produced dose-related increases in pulmonary and systemic arterial pressure. Losartan and candesartan, in the doses studied, decreased or abolished responses to angiotensin II. Losartan, but not candesartan, and only in a higher dose, produced small, but statistically significant, reductions in pressor responses to U46619 and to norepinephrine in the pulmonary and systemic vascular beds. Furthermore, losartan significantly reduced arachidonic acid-induced platelet aggregation, whereas candesartan had no effect. Pressor responses to angiotensin II were not changed by thromboxane and alpha-adrenergic receptor antagonists, or by cyclooxygenase and NO synthase inhibitors. These results show that losartan and candesartan are potent selective AT1 receptor antagonists in the pulmonary and systemic vascular beds and that losartan can attenuate thromboxane and alpha-adrenergic responses when administered at a high dose, whereas candesartan in the highest dose studied had no effect on responses to U46619 or to norepinephrine. The present data show that the effects of losartan and candesartan on vasoconstrictor responses are different and that pulmonary and systemic pressor responses to angiotensin II are not modulated or mediated by the release of cyclooxygenase products, activation of TP receptors, or the release of NO in the anesthetized rat. 相似文献
19.
B D Nossaman P A Dabisch J T Liles S R Baber H C Champion A D Kaye C-J Feng M Anwar T J Bivalacqua J A Santiago B J De Witt P J Kadowitz 《Journal of applied physiology》2004,96(2):455-462
The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release. 相似文献
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