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排序方式: 共有91条查询结果,搜索用时 31 毫秒
1.
Nuclear magnetic resonance (NMR) spectroscopy has evolved into a powerful tool for fragment-based drug discovery over the last two decades. While NMR has been traditionally used to elucidate the three-dimensional structures and dynamics of biomacromolecules and their interactions, it can also be a very valuable tool for the reliable identification of small molecules that bind to proteins and for hit-to-lead optimization. Here, we describe the use of NMR spectroscopy as a method for fragment-based drug discovery and how to most effectively utilize this approach for discovering novel therapeutics based on our experience. 相似文献
2.
Combined monte carlo and molecular dynamics simulation of fully hydrated dioleyl and palmitoyl-oleyl phosphatidylcholine lipid bilayers 总被引:1,自引:1,他引:0 下载免费PDF全文
We have applied a new equilibration procedure for the atomic level simulation of a hydrated lipid bilayer to hydrated bilayers of dioleyl-phosphatidylcholine (DOPC) and palmitoyl-oleyl phosphatidylcholine (POPC). The procedure consists of alternating molecular dynamics trajectory calculations in a constant surface tension and temperature ensemble with configurational bias Monte Carlo moves to different regions of the configuration space of the bilayer in a constant volume and temperature ensemble. The procedure is applied to bilayers of 128 molecules of POPC with 4628 water molecules, and 128 molecules of DOPC with 4825 water molecules. Progress toward equilibration is almost three times as fast in central processing unit (CPU) time compared with a purely molecular dynamics (MD) simulation. Equilibration is complete, as judged by the lack of energy drift in 200-ps runs of continuous MD. After the equilibrium state was reached, as determined by agreement between the simulation volume per lipid molecule with experiment, continuous MD was run in an ensemble in which the lateral area was restrained to fluctuate about a mean value and a pressure of 1 atm applied normal to the bilayer surface. Three separate continuous MD runs, 200 ps in duration each, separated by 10,000 CBMC steps, were carried out for each system. Properties of the systems were calculated and averaged over the three separate runs. Results of the simulations are presented and compared with experimental data and with other recent simulations of POPC and DOPC. Analysis of the hydration environment in the headgroups supports a mechanism by which unsaturation contributes to reduced transition temperatures. In this view, the relatively horizontal orientation of the unsaturated bond increases the area per lipid, resulting in increased water penetration between the headgroups. As a result the headgroup-headgroup interactions are attenuated and shielded, and this contributes to the lowered transition temperature. 相似文献
3.
Using an NMR-based screen, a series of novel phosphotyrosine mimetics were discovered that bind to the SH2 domain of Lck. These compounds may serve as useful leads for the design of nonpeptide inhibitors of SH2 domains with improved bioavailability and metabolic stability compared to the natural ligands that contain phosphotyrosine. 相似文献
4.
Hong Wang Matthias Eberstadt Edward T. Olejniczak Robert P. Meadows Stephen W. Fesik 《Journal of biomolecular NMR》1998,12(3):443-446
A mixture of dilauroyl phosphatidylcholine (DLPC) and 3-(cholamidopropyl)dimethylammonio-2-hydroxyl-1-propane sulfonate (CHAPSO) in water forms disc shaped bicelles that become ordered at high magnetic fields over a wide range of temperatures. As illustrated for the FK506 binding protein (FKBP), large residual dipolar couplings can be measured for proteins dissolved in low concentrations (5% w/v) of a DLPC/CHAPSO medium at a molar ratio of 4.2:1. This system is especially useful for measuring residual dipolar couplings for molecules that are only stable at low temperatures. 相似文献
5.
A general approach is illustrated for providing detailed structural information on large enzyme/inhibitor complexes using NMR spectroscopy. The method involves the use of isotopically labeled ligands to simplify two-dimensional NOE spectra of large molecular complexes by isotope-editing techniques. With this approach, the backbone and side-chain conformations (at the P2 and P3 sites) of a tightly bound inhibitor of porcine pepsin have been determined. In addition, structural information on the active site of pepsin has been obtained. Due to the sequence homology between porcine pepsin and human renin, this structural information may prove useful for modeling renin/inhibitor complexes with the ultimate goal of designing more effective renin inhibitors. Moreover, this general approach can be applied to study other biological systems of interest such as other enzyme/inhibitor complexes, ligands bound to soluble receptors, and enzyme/substrate interactions. 相似文献
6.
The conformational properties of an analog of atrial naturiuretic factor, [Pro-10] ANF(7-23), were examined in H2O, H2O/DMSO-d6 (2/1), and DMSO-d6 using two-dimensional nmr techniques. The sequence differs from the native peptide by the absence of the exocyclic N- and C-terminal residues, and the substitution of a proline for a glycine at position 10—a modification expected to reduce the conformational flexibility of this analog. The backbone proton nmr resonances were assigned from two-dimensional correlated spectroscopy (2D-COSY), relayed COSY, and 2D nuclear Overhàuser enhancement (NOE) experiments, and the solution conformation was evaluated from vicinal spin–spin coupling constants and NOE data. Despite the substitution of a proline in the sequence, [Pro-10] ANF(7-23) exhibits a considerable amount of flexibility in all of the solvents employed. 相似文献
7.
NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP 总被引:29,自引:0,他引:29
Sun C Cai M Meadows RP Xu N Gunasekera AH Herrmann J Wu JC Fesik SW 《The Journal of biological chemistry》2000,275(43):33777-33781
The inhibitor of apoptosis proteins (IAPs) regulate the caspase family of cysteine proteases, which play an important role in the execution of programmed cell death. Human X-linked inhibitor of apoptosis protein (XIAP) is a potent inhibitor of caspases-3, -7, and -9. Here we show that the Bir3 domain is the minimal region of XIAP that is needed for potent caspase-9 inhibition. The three-dimensional structure of the Bir3 domain of XIAP, determined by NMR spectroscopy, resembles a classical zinc finger and consists of five alpha-helices, a three-stranded beta-sheet, and a zinc atom chelated to three cysteines and one histidine. The structure of the Bir3 domain is similar to that of the Bir2 domain of XIAP but differs from the previously determined structure of the Bir3 domain of MIHB. Based on site-directed mutagenesis, we have identified the regions of the Bir3 domain of XIAP that are important for inhibiting caspase-9. Despite the structural similarities of the Bir2 and Bir3 domain of XIAP, a different set of residues were found to be critical for inhibiting the individual caspases. These results suggest that XIAP inhibits caspase-3 and caspase-9 in a different manner. 相似文献
8.
The Bcl-2 family of proteins play a pivotal role in the regulation of programmed cell death. One of the postulated mechanisms for the function of these proteins involves the formation of ion channels in membranes. As a first step to structurally characterize these proteins in a membrane environment, we investigated the structure of a Bcl-x(L) mutant protein when incorporated into small detergent micelles. This form of Bcl-x(L) lacks the loop (residues 49-88) between helix 1 and helix 2 and the putative C-terminal transmembrane helix (residues 214-237). Below the critical micelle concentration (CMC), Bcl-x(L) binds detergents in the hydrophobic groove that binds to pro-apoptotic proteins. However, above the CMC, Bcl-x(L) undergoes a dramatic conformational change. Using NMR methods, we characterized the secondary structure of Bcl-x(L) in the micelle-bound form. Like Bcl-x(L) in aqueous solution, the structure of the protein when dissolved in dodecylphosphocholine (DPC) micelles consists of several alpha-helices separated by loops. However, the length and position of the individual helices of Bcl-x(L) in micelles differ from those in aqueous solution. The location of Bcl-x(L) within the micelle was examined from the analysis of protein-detergent NOEs and limited proteolysis. In addition, the mobility of the micelle-bound form of Bcl-x(L) was investigated from NMR relaxation measurements. On the basis of these studies, a model is proposed for the structure, dynamics, and location of Bcl-x(L) in micelles. In this model, Bcl-x(L) has a loosely packed, dynamic structure in micelles, with helices 1 and 6 and possibly helix 5 partially buried in the hydrophobic interior of the micelle. Other parts of the protein are located near the surface or on the outside of the micelle. 相似文献
9.
14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation 总被引:15,自引:0,他引:15
The Bcl-2 homology 3 (BH3) domain of prodeath Bcl-2 family members mediates their interaction with prosurvival Bcl-2 family members and promotes apoptosis. We report that survival factors trigger the phosphorylation of the proapoptotic Bcl-2 family member BAD at a site (Ser-155) within the BAD BH3 domain. When BAD is bound to prosurvival Bcl-2 family members, BAD Ser-155 phosphorylation requires the prior phosphorylation of Ser-136, which recruits 14-3-3 proteins that then function to increase the accessibility of Ser-155 to survival-promoting kinases. Ser-155 phosphorylation disrupts the binding of BAD to prosurvival Bcl-2 proteins and thereby promotes cell survival. These findings define a mechanism by which survival signals inactivate a proapoptotic Bcl-2 family member, and suggest a role for 14-3-3 proteins as cofactors that regulate sequential protein phosphorylation events. 相似文献
10.
For several species of lepidoptera, most of the approximately 350-bp
mitochondrial control-region sequences were determined. Six of these
species are in one genus, Jalmenus; are closely related; and are believed
to have undergone recent rapid speciation. Recent speciation was supported
by the observation of low interspecific sequence divergence. Thus, no
useful phylogeny could be constructed for the genus. Despite a surprising
conservation of control-region length, there was little conservation of
primary sequences either among the three lepidopteran genera or between
lepidoptera and Drosophila. Analysis of secondary structure indicated only
one possible feature in common--inferred stem loops with higher-than-random
folding energies-- although the positions of the structures in different
species were unrelated to regions of primary sequence similarity. We
suggest that the conserved, short length of control regions is related to
the observed lack of heteroplasmy in lepidopteran mitochondrial genomes. In
addition, determination of flanking sequences for one Jalmenus species
indicated (i) only weak support for the available model of insect 12S rRNA
structure and (ii) that tRNA translocation is a frequent event in the
evolution of insect mitochondrial genomes.
相似文献