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991.
992.
Inositol 1,4,5‐trisphosphate receptor (InsP3R) is an intracellular Ca2+‐release channel activated by binding of inositol 1,4,5‐trisphosphate (InsP3) to the InsP3 binding core (IBC). Structural change in the IBC upon InsP3 binding is the key process in channel pore opening. In this study, we performed molecular dynamics (MD) simulations of the InsP3‐free form of the IBC, starting with removal of InsP3 from the InsP3‐bound crystal structure, and obtained the structural ensemble of the InsP3‐free form of the IBC. The simulation revealed that the two domains of the IBC largely fluctuate around the average structure with the hinge angle opened 17° more than in the InsP3‐bound form, and the twist angle rotated by 45°, forming interdomain contacts that are different from those in the bound form. The InsP3 binding loop was disordered. The InsP3‐free form thus obtained was reproduced four times in simulations started from a fully extended configuration of the two domains. Simulations beginning with the fully extended form indicated that formation of a salt bridge between Arg241 and Glu439 is crucial for stabilizing the closed form of the two domains. Mutation of Arg241 to Gln prevented formation of the compact structure by the two domains, but the fully flexible domain arrangement was maintained. Thus, the Arg241‐Glu439 salt bridge determines the flexibility of the InsP3‐free form of the IBC.Proteins 2013; 81:1699–1708. © 2013 Wiley Periodicals, Inc. 相似文献
993.
Understanding the effects of mutation on pH‐dependent protein binding affinity is important in protein design, especially in the area of protein therapeutics. We propose a novel method for fast in silico mutagenesis of protein–protein complexes to calculate the effect of mutation as a function of pH. The free energy differences between the wild type and mutants are evaluated from a molecular mechanics model, combined with calculations of the equilibria of proton binding. The predicted pH‐dependent energy profiles demonstrate excellent agreement with experimentally measured pH‐dependency of the effect of mutations on the dissociation constants for the complex of turkey ovomucoid third domain (OMTKY3) and proteinase B. The virtual scanning mutagenesis identifies all hotspots responsible for pH‐dependent binding of immunoglobulin G (IgG) to neonatal Fc receptor (FcRn) and the results support the current understanding of the salvage mechanism of the antibody by FcRn based on pH‐selective binding. The method can be used to select mutations that change the pH‐dependent binding profiles of proteins and guide the time consuming and expensive protein engineering experiments. As an application of this method, we propose a computational strategy to search for mutations that can alter the pH‐dependent binding behavior of IgG to FcRn with the aim of improving the half‐life of therapeutic antibodies in the target organism. © Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
994.
Biao Cheng Hao Gong Xiaochao Li Yue Sun Hong Chen Xin Zhang Qian Wu Ling Zheng Kun Huang 《Proteins》2013,81(4):613-621
The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as one of the causative factors of type 2 diabetes mellitus (T2DM). Salvia miltiorrhiza (Danshen), one of the most commonly used of traditional Chinese medicines, is often used in Compound Recipes for treating diabetes, however with unclear mechanisms. Since salvianolic acid B (SalB) is the most abundant bioactive ingredient of salvia miltiorrhiza water‐extract. In this study, we tested whether SalB has any effect on the amyloidogenicity of hIAPP. Our results clearly suggest that SalB can significantly inhibit the formation of hIAPP amyloid and disaggregate hIAPP fibrils. Furthermore, photo‐crosslinking based oligomerization studies suggest SalB significantly suppresses the toxic oligomerization of hIAPP monomers. Cytotoxicity protection effects on pancreatic INS‐1 cells by SalB were also observed using MTT‐based assays, potentially due to the inhibition on the membrane disruption effects and attenuated mitochondria impairment induced by hIAPP. These results provide evidence that SalB may further be studied on the possible pharmacological treatment for T2DM. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
995.
Claudia C. Cornilescu Gabriel Cornilescu Hongyu Rao Sarah F. Porter Marco Tonelli Michele L. DeRider John L. Markley Fariba M. Assadi‐Porter 《Proteins》2013,81(6):919-925
The sweet protein brazzein, a member of the Csβα fold family, contains four disulfide bonds that lend a high degree of thermal and pH stability to its structure. Nevertheless, a variable temperature study has revealed that the protein undergoes a local, reversible conformational change between 37 and 3°C with a midpoint about 27°C that changes the orientations and side‐chain hydrogen bond partners of Tyr8 and Tyr11. To test the functional significance of this effect, we used NMR saturation transfer to investigate the interaction between brazzein and the amino terminal domain of the sweet receptor subunit T1R2; the results showed a stronger interaction at 7°C than at 37°C. Thus the low temperature conformation, which alters the orientations of two loops known to be critical for the sweetness of brazzein, may represent the bound state of brazzein in the complex with the human sweet receptor. Proteins 2013; © 2012 Wiley Periodicals, Inc. 相似文献
996.
997.
Masato Hayakawa Tatsuya Ohyama Yoko Yamaguchi Shingo Iwabuchi Tomohiko Nakagawa Tamie Nakajima 《Molecular simulation》2013,39(9):644-656
To elucidate the specific interactions between the peroxisome proliferator-activated receptor (PPARα) and ligand GW409544 (GW), we obtained the solvated structures of the PPARα+GW complexes for human, mouse and rat by classical molecular mechanics calculations, and investigated their electronic properties by ab initio fragment molecular orbital calculations. The results indicate that the positively charged amino acids (Lys and Arg) of PPARα make a major contribution to the binding between PPARα and GW. In addition, it was clarified that Ser280 and Tyr314 of human and rat PPARα have a large attractive interaction with GW, while Ser280, Tyr314 and His440 of mouse PPARα have large interaction. These results on the difference in specific interactions between human and mouse/rat PPARα will be useful for predicting the effects of new chemicals on the human body based on the biomedical studies for the experimental animals such as mouse and rat. 相似文献
998.
《Journal of liposome research》2013,23(2-3):179-195
AbstractA novel lipophilic conjugate of folate, folate-PEG-Chol, was synthesized and evaluated for receptor-mediated targeting of liposomes to tumor cells. Liposomes composed of DSPC/Chol/PEG-DSPE/folate-PEG-Chol (60/ 34/5/1, m/m) were taken up by cultured folate receptor-bearing KB cells via a saturable mechanism. Cellular binding of these liposomes could be competitively inhibited by free folic acid with an IC50 of 0.39 mM, indicating an extraordinarily high binding affinity. Fluorescence micrographs of KB cells treated with targeted liposomes encapsulating calcein showed that they were distributed both on the cell surface and in intracellular vesicular compartments. Targeted liposomes carrying doxorubicin were shown to be 38 times more toxic to KB cells than non-targeted control liposomes. A biodistribution study in receptor-positive tumor-bearing C57BL/6 mice showed no significant differences between the tumor uptake of folate-PEG-liposomes and non-targeted control liposomes. This study has demonstrated that cholesterol could be used as an alternative to phospholipids as an effective anchor for incorporation of a targeting ligand into liposomes. 相似文献
999.
Nadrian C. Seeman 《Journal of biomolecular structure & dynamics》2013,31(1):11-34
Abstract The simplest form of macromolecular design involves the ligation of nucleic acids. Recent results on the concatenation of nucleic acid junctions show that these molecules can act as fairly rigid macromolecular valence clusters on the nanometer scale. These clusters can be joined to form closed stick figures in which each edge is double helical DNA or RNA and each vertex is a nucleic acid junction. The geometrical criteria for forming discrete-closed and periodic structures from these components are established. The helicity of each edge limits the possible structures that can be formed. The formation of a periodic array from nucleic acid junction building blocks is compared with the crystallization of molecular systems. This comparison leads to a new interpretation of the nature of order in the solid state for molecular crystals. The suggestion is made that the structure of a solid molecular system described by the fewest unique orthogonal (Fourier) components is the one which will be entropically favored, since it contains the least information. This is the crystalline state, with a small number of molecules per asymmetric unit. The free energy from the proposed entropie driving force responsible for this behavior is available, in principle, to correct small deviations from ideality in forming covalent crystals from nucleic acid junction components, as well as in non-bonded molecular systems. Nucleic acid junction periodic arrays provide an appropriate vehicle with which to test this interpretation. 相似文献
1000.
Goutam Gupta M. M. Dhingra Ramaswamy H. Sarma 《Journal of biomolecular structure & dynamics》2013,31(1):97-113
Abstract It is now very well recognized that the DNA double helix is conformationally pluralistic and that this flexibility is derived from internal motions due to backbone torsions. But what is less apparent is that such internal motions can occur in a correlated fashion and express themselves in a wide variety of structural motifs and phenomena. For example, flexibility inherent in the DNA molecule can lead to a family of Z-DNA, LZ1 and LZ2 being the two extremes and correlated internal motion can cause LZ1?LZ2 transition. More interestingly, such motions manifest themselves as breathing modes on the DNA lattice resulting in the sequence specific intercalation sites. Following a detailed stereochemical analyses we observed that the intercalation site for ethidium is located at the dCpdG sequence of the intercalated LZ1 helix (LZ1*) while that for actinomycin D is located at the dGpdC sequence of the intercalated LZ2 helix (LZ2*). From the stereochemistry of the drug binding we make experimentally testable predictions which are in fact supported by a few recent experimental studies. These studies also show that a left-handed intercalated B-DNA model is a viable intermediate in the Z to B transition which can hold the drug with binding energy comparable to that of the intercalated right-handed B-DNA. 相似文献