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81.
82.
David Shirvanyants Srinivas RamachandranYingwu Mei Le XuGerhard Meissner Nikolay V. Dokholyan 《Biophysical journal》2014
Ryanodine receptors (RyR) are calcium release channels, playing a major role in the regulation of muscular contraction. Mutations in skeletal muscle RyR (RyR1) are associated with congenital diseases such as malignant hyperthermia and central core disease (CCD). The absence of high-resolution structures of RyR1 has limited our understanding of channel function and disease mechanisms at the molecular level. Previously, we have reported a hypothetical structure of the RyR1 pore-forming region, obtained by homology modeling and supported by mutational scans, electrophysiological measurements, and cryo-electron microscopy. Here, we utilize the expanded model encompassing six transmembrane helices to calculate the RyR1 pore region conductance, to analyze its structural stability, and to hypothesize the mechanism of the Ile4897 CCD-associated mutation. The calculated conductance of the wild-type RyR1 suggests that the proposed pore structure can sustain ion currents measured in single-channel experiments. We observe a stable pore structure on timescales of 0.2 μs, with multiple cations occupying the selectivity filter and cytosolic vestibule, but not the inner chamber. We further suggest that stability of the selectivity filter critically depends on the interactions between the I4897 residue and several hydrophobic residues of the neighboring subunit. Loss of these interactions in the case of polar substitution I4897T results in destabilization of the selectivity filter, a possible cause of the CCD-specific reduced Ca2+ conductance. 相似文献
83.
Parasuram R Lee JS Yin P Somarowthu S Ondrechen MJ 《Journal of bioinformatics and computational biology》2010,8(Z1):1-15
A new approach to the functional classification of protein 3D structures is described with application to some examples from structural genomics. This approach is based on functional site prediction with THEMATICS and POOL. THEMATICS employs calculated electrostatic potentials of the query structure. POOL is a machine learning method that utilizes THEMATICS features and has been shown to predict accurate, precise, highly localized interaction sites. Extension to the functional classification of structural genomics proteins is now described. Predicted functionally important residues are structurally aligned with those of proteins with previously characterized biochemical functions. A 3D structure match at the predicted local functional site then serves as a more reliable predictor of biochemical function than an overall structure match. Annotation is confirmed for a structural genomics protein with the ribulose phosphate binding barrel (RPBB) fold. A putative glucoamylase from Bacteroides fragilis (PDB ID 3eu8) is shown to be in fact probably not a glucoamylase. Finally a structural genomics protein from Streptomyces coelicolor annotated as an enoyl-CoA hydratase (PDB ID 3g64) is shown to be misannotated. Its predicted active site does not match the well-characterized enoyl-CoA hydratases of similar structure but rather bears closer resemblance to those of a dehalogenase with similar fold. 相似文献
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Dimitrov JD Christophe OD Kang J Repessé Y Delignat S Kaveri SV Lacroix-Desmazes S 《Biochemistry》2012,51(20):4108-4116
Factor VIII (FVIII) is a glycoprotein that plays an important role in the intrinsic pathway of coagulation. In circulation, FVIII is protected upon binding to von Willebrand factor (VWF), a chaperone molecule that regulates its half-life, distribution, and activity. Despite the biological significance of this interaction, its molecular mechanisms are not fully characterized. We determined the equilibrium and activation thermodynamics of the interaction between FVIII and VWF. The equilibrium affinity determined by surface plasmon resonance was temperature-dependent with a value of 0.8 nM at 35 °C. The FVIII-VWF interaction was characterized by very fast association (8.56 × 10(6) M(-1) s(-1)) and fast dissociation (6.89 × 10(-3) s(-1)) rates. Both the equilibrium association and association rate constants, but not the dissociation rate constant, were dependent on temperature. Binding of FVIII to VWF was characterized by favorable changes in the equilibrium and activation entropy (TΔS° = 89.4 kJ/mol, and -TΔS(++) = -8.9 kJ/mol) and unfavorable changes in the equilibrium and activation enthalpy (ΔH° = 39.1 kJ/mol, and ΔH(++) = 44.1 kJ/mol), yielding a negative change in the equilibrium Gibbs energy. Binding of FVIII to VWF in solid-phase assays demonstrated a high sensitivity to acidic pH and a sensitivity to ionic strength. Our data indicate that the interaction between FVIII and VWF is mediated mainly by electrostatic forces, and that it is not accompanied by entropic constraints, suggesting the absence of conformational adaptation but the presence of rigid "pre-optimized" binding surfaces. 相似文献
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Monocrotophos inhibited monoamine oxidase (MAO) activity both in vitro and in vivo in liver, kidney and brain areas of albino rats. In vitro effect was more pronounced than the in vivo effect. During in vivo daily treatment with sublethal doses of Monocrotophos, the MAO activity was significantly inhibited after 1h to 7 days of treatments. Later recovery of inhibition was noticed which might be attributed to the enhanced absorption of Monocrotophos to protein and fat bodies or enhanced metabolic dispositional mechanisms. Brain areas exhibit varied responses to Monocrotophos toxicity. 相似文献
89.
Harsh Chauhan Srinivas A. Desai Paramjit Khurana 《Plant Cell, Tissue and Organ Culture》2007,91(3):191-199
An efficient genotype independent, in vitro regeneration system was developed for nine popular Indian wheat cultivars, three
each of Triticum aestivum L. viz., CPAN1676, HD2329 and PBW343, Triticum durum Desf. viz., PDW215, PDW233 and WH896, and Triticum dicoccum Schrank. Schubl. viz., DDK1001, DDK1025 and DDK1029, by manipulating the concentration and time of exposure to the growth
regulator, thidiazuron (TDZ). A total of 18 (for immature inflorescence and embryo explant) and six (for mature embryo explant)
different combinations of growth regulators were tried for callusing and regeneration, respectively. Media combination with
low concentration of TDZ (2.2 μM) in combination to auxin and/or cytokinin (depending upon culture stage), was found to be
effective for immature and mature explants. Compact, nodular and highly embryogenic calli were obtained by using immature
embryo, immature inflorescence and mature embryo explants, and regeneration frequency up to 25 shoots/explant with an overall
80% regeneration was achieved. Comparable regeneration frequency was achieved for mature embryo explants. No separate hormone
combination for rooting was required and plantlets ready to transfer to soil could be obtained in a short period of 8–10 weeks.
This protocol can be used for raising transgenic plants for functional genomics analysis of agronomically important traits
in the three species of wheat. 相似文献
90.
Mitogen-activated protein kinase kinase-4 promotes cell survival by decreasing PTEN expression through an NF kappa B-dependent pathway 总被引:2,自引:0,他引:2
Xia D Srinivas H Ahn YH Sethi G Sheng X Yung WK Xia Q Chiao PJ Kim H Brown PH Wistuba II Aggarwal BB Kurie JM 《The Journal of biological chemistry》2007,282(6):3507-3519