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991.
Ariane Wagner Francesca Di Bartolomeo Isabella Klein Claudia Hrastnik Kim Nguyen Doan Thomas Becker Günther Daum 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(2):117-125
Phosphatidylserine decarboxylase 1 (Psd1p) catalyzes the formation of the majority of phosphatidylethanolamine (PE) in the yeast Saccharomyces cerevisiae. Psd1p is localized to mitochondria, anchored to the inner mitochondrial membrane (IMM) through membrane spanning domains and oriented towards the mitochondrial intermembrane space. We found that Psd1p harbors at least two inner membrane-associated domains, which we named IM1 and IM2. IM1 is important for proper orientation of Psd1p within the IMM (Horvath et al., J. Biol. Chem. 287 (2012) 36744–55), whereas it remained unclear whether IM2 is important for membrane-association of Psd1p. To discover the role of IM2 in Psd1p import, processing and assembly into the mitochondria, we constructed Psd1p variants with deletions in IM2. Removal of the complete IM2 led to an altered topology of the protein with the soluble domain exposed to the matrix and to decreased enzyme activity. Psd1p variants lacking portions of the N-terminal moiety of IM2 were inserted into IMM with an altered topology. Psd1p variants with deletions of C-terminal portions of IM2 accumulated at the outer mitochondrial membrane and lost their enzyme activity. In conclusion we showed that IM2 is essential for full enzymatic activity, maturation and correct integration of yeast Psd1p into the inner mitochondrial membrane. 相似文献
992.
Sam L. Ivry Nicole O. Meyer Michael B. Winter Markus F. Bohn Giselle M. Knudsen Anthony J. O'Donoghue Charles S. Craik 《Protein science : a publication of the Protein Society》2018,27(3):584-594
Enzymes that modify the proteome, referred to as post‐translational modifying (PTM) enzymes, are central regulators of cellular signaling. Determining the substrate specificity of PTM enzymes is a critical step in unraveling their biological functions both in normal physiological processes and in disease states. Advances in peptide chemistry over the last century have enabled the rapid generation of peptide libraries for querying substrate recognition by PTM enzymes. In this article, we highlight various peptide‐based approaches for analysis of PTM enzyme substrate specificity. We focus on the application of these technologies to proteases and also discuss specific examples in which they have been used to uncover the substrate specificity of other types of PTM enzymes, such as kinases. In particular, we highlight our multiplex substrate profiling by mass spectrometry (MSP‐MS) assay, which uses a rationally designed, physicochemically diverse library of tetradecapeptides. We show how this method has been applied to PTM enzymes to uncover biological function, and guide substrate and inhibitor design. We also briefly discuss how this technique can be combined with other methods to gain a systems‐level understanding of PTM enzyme regulation and function. 相似文献
993.
Solar Cells: Hot‐Substrate Deposition of Hole‐ and Electron‐Transport Layers for Enhanced Performance in Perovskite Solar Cells (Adv. Energy Mater. 2/2018)
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994.
Alex Reichenbach Romana Stark Mathieu Mequinion Raphael R.G. Denis Jeferson F. Goularte Rachel E. Clarke Sarah H. Lockie Moyra B. Lemus Greg M. Kowalski Clinton R. Bruce Cheng Huang Ralf B. Schittenhelm Randall L. Mynatt Brian J. Oldfield Matthew J. Watt Serge Luquet Zane B. Andrews 《Cell reports》2018,22(7):1745-1759
995.
996.
Conformational substates in enzyme mechanism: the 120 K structure of alpha-lytic protease at 1.5 A resolution. 总被引:2,自引:2,他引:0
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Insight into the dynamic properties of alpha-lytic protease (alpha LP) has been obtained through the use of low-temperature X-ray crystallography and multiple-conformation refinement. Previous studies of alpha LP have shown that the residues around the active site are able to move significantly to accommodate substrates of different sizes. Here we show a link between the ability to accommodate ligands and the dynamics of the binding pocket. Although the structure of alpha LP at 120 K has B-factors with a uniformly low value of 4.8 A2 for the main chain, four regions stand out as having significantly higher B-factors. Because thermal motion should be suppressed at cryogenic temperatures, the high B-factors are interpreted as the result of trapped conformational substates. The active site residues that are perturbed during accommodation of different substrates are precisely those showing conformational substates, implying that substrate binding selects a subset of conformations from the ensemble of accessible states. To better characterize the precise nature of these substates, a protein model consisting of 16 structures has been refined and evaluated. The model reveals a number of features that could not be well-described by conventional B-factors: for example, 40% of the main-chain residue conformations are distributed asymmetrically or in discrete clusters. Furthermore, these data demonstrate an unexpected correlation between motions on either side of the binding pocket that we suggest is a consequence of "dynamic close packing." These results provide strong evidence for the role of protein dynamics in substrate binding and are consistent with the results of dynamic studies of ligand binding in myoglobin and ribonuclease A. 相似文献
997.
I. T. Weber R. W. Harrison 《Protein science : a publication of the Protein Society》1997,6(11):2365-2374
Molecular models of Rous sarcoma virus (RSV) protease and 20 peptide substrates with single amino acid substitutions at positions from P4 to P3', where the scissile bond is between P1 and P1'. were built and compared with kinetic measurements. The unsubstituted peptide substrate. Pro-Ala-Val-Ser-Leu-Ala-Met-Thr, represents the NC-PR cleavage site of RSV protease. Models were built of two intermediates in the catalytic reaction, RSV protease with peptide substrate and with the tetrahedral intermediate. The energy minimization used an algorithm that increased the speed and eliminated a cutoff for nonbonded interactions. The calculated protease-substrate interaction energies showed correlation with the relative catalytic efficiency of peptide hydrolysis. The calculated interaction energies for the 8 RSV protease-substrate models with changes in P1 to P1' next to the scissile bond gave the highest correlation coefficient of 0.79 with the kinetic measurements, whereas all 20 substrates showed the lower, but still significant correlation of 0.46. Models of the tetrahedral reaction intermediates gave a correlation of 0.72 for the 8 substrates with changes next to the scissile bond, whereas a correlation coefficient of only 0.34 was observed for all 20 substrates. The differences between the energies calculated for the tetrahedral intermediate and the bound peptide gave the most significant correlation coefficients of 0.90 for models with changes in P1 and P1', and 0.56 for all substrates. These results are compared to those from similar calculations on HIV-1 protease and discussed in relation to the rate-limiting steps in the catalytic mechanism and the entropic contributions. 相似文献
998.
Structure of a pancreatic alpha-amylase bound to a substrate analogue at 2.03 A resolution. 总被引:1,自引:1,他引:0
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M. Qian S. Spinelli H. Driguez F. Payan 《Protein science : a publication of the Protein Society》1997,6(11):2285-2296
The structure of pig pancreatic alpha-amylase in complex with carbohydrate inhibitor and proteinaceous inhibitors is known but the successive events occurring at the catalytic center still remain to be elucidated. The X-ray structure analysis of a crystal of pig pancreatic alpha-amylase (PPA, EC 3.2.1.1.) soaked with an enzyme-resistant substrate analogue, methyl 4,4'-dithio-alpha-maltotrioside, showed electron density corresponding to the binding of substrate analogue molecules at the active site and at the "second binding site." The electron density observed at the active site was interpreted in terms of overlapping networks of oligosaccharides, which show binding of substrate analogue molecules at subsites prior to and subsequent to the cleavage site. A weaker patch of density observed at subsite -1 (using a nomenclature where the site of hydrolysis is taken to be between subsites -1 and +1) was modeled with water molecules. Conformational changes take place upon substrate analogue binding and the "flexible loop" that constitutes the surface edge of the active site is observed in a specific conformation. This confirms that this loop plays an important role in the recognition and binding of the ligand. The crystal structure was refined at 2.03 A resolution, to an R-factor of 16.0 (Rfree, 18.5). 相似文献
999.
Summary
N--peptidyl-l-lysine p-nitroanilides may easily be prepared under mild conditions starting from commercially available H-Lys(Boc)-pNA (3) and N--tritylated amino acids using CF3-PyBOP (1) as condensating reagent. An illustration of this approach was given by the synthesis of the novel promising plasmin substrate isovaleryl-l-phenylalanyl-l-lysine p-nitroanilide hydrochloride (6).Abbreviations Boc
t-butyloxycarbonyl
- CF3-PyBOP
[6-(trifluoromethyl)benzotriazol-l-yloxy]tris(pyrrolidino)phosphonium hexafluorophosphate
- DEA
diethylamine
- DIEA
N,N-diisopropylethylamine
- Fmoc
fluoren-9-yl-methoxycarbonyl
- Isoval
isovaleryl
- pNA
p-nitroanilide
- Trt
trityl
- Z
benzyloxycarbonyl 相似文献
1000.
Supply of 1, 2, 5, 10 or 20 mM nitrate to detached roots, scutella or shoots from 5- to 6-d-old Zea mays L. seedlings increased
in vitro nitrate reductase (NR) activity in all the organs and NADPH specific NR (NADPH:NR) activity in roots and scutella
but not in the shoots. Usually 2 to 5 mM nitrate supported maximum enzyme activity, the higher concentration did not increase
it further. The protein content in the roots, scutella and shoots increased up to 5, 2 and 20 mM medium nitrate, respectively.
Nitrate uptake also increased with increasing nitrate concentration in roots and shoots, but it increased only slightly in
the scutella. In both roots and scutella, methionine sulfoximine had no effect, while cycloheximide and tungstate abolished
nitrate induced NADH:NR activity completely and NADPH:NR partially. Methionine sulfoximine increased nitrate uptake by roots
and scutella slightly, but other inhibitors had no effect. The depletion of dissolved oxygen from the medium was lower in
the presence of nitrate than in its absence or in the presence of ammonium, especially in the scutella.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献