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651.
Brownian dynamics simulations of molecular recognition in an antibody-antigen system. 总被引:2,自引:1,他引:1 下载免费PDF全文
R. E. Kozack S. Subramaniam 《Protein science : a publication of the Protein Society》1993,2(6):915-926
The crystal structure for an antibody-antigen system, that of the anti-hen egg lysozyme monoclonal antibody HyHEL-5 complexed to lysozyme, is used as the starting point for computer simulations of diffusional encounters between the two proteins. The investigation consists of two parts: first, the linearized Poisson-Boltzmann equation is solved to determine the long-range electrostatic forces between antibody and antigen, and then, the relative motion as influenced by these forces is modeled within Brownian motion theory. The effects of various point mutations on the calculated reaction rate are considered. It is found that charged residues close to the binding site exert the greatest influence in steering the proteins into a configuration favorable for their binding, while more distant mutations are qualitatively described by the Smoluchowski model for the mutual diffusion of two uniformly charged spheres. The antibody residues involved in forming salt links with the lysozyme, Glu-H35 and Glu-H50, appear to be particularly important in electrostatic steering, as neutralization of both of them yields reaction rates that are two to three orders of magnitude below those of wild-type rates. The relative rates obtained from the simulations can be tested through kinetic measurements on mutant protein complexes. Kinetically efficient partners can also be designed and constructed through directed mutagenesis. 相似文献
652.
Pal A Chu UB Ramachandran S Grawoig D Guo LW Hajipour AR Ruoho AE 《The Journal of biological chemistry》2008,283(28):19646-19656
sigma-1 receptors represent unique binding sites that are capable of interacting with a wide range of compounds to mediate different cellular events. The composition of the ligand binding site of this receptor is unclear, since no NMR or crystal structures are available. Recent studies in our laboratory using radiolabeled photoreactive ligands suggested that the steroid binding domain-like I (SBDLI) (amino acids 91-109) and the steroid binding domain-like II (SBDLII) (amino acids 176-194) regions are involved in forming the ligand binding site(s) ( Chen, Y., Hajipour, A. R., Sievert, M. K., Arbabian, M., and Ruoho, A. E. (2007) Biochemistry 46, 3532-3542 ; Pal, A., Hajipour, A. R., Fontanilla, D., Ramachandran, S., Chu, U. B., Mavlyutov, T., and Ruoho, A. E. (2007) Mol. Pharmacol. 72, 921-933 ). In this report, we have further addressed this issue by utilizing our previously developed sulfhydryl-reactive, cleavable, radioiodinated photocross-linking reagent: methanesulfonothioic acid, S-((4-(4-amino-3-[125I]iodobenzoyl) phenyl)methyl) ester (Guo, L. W., Hajipour, A. R., Gavala, M. L., Arbabian, M., Martemyanov, K. A., Arshavsky, V. Y., and Ruoho, A. E. (2005) Bioconjugate Chem. 16, 685-693). This photoprobe was shown to derivatize the single cysteine residues as mixed disulfides at position 94 in the SBDLI region of the wild type guinea pig sigma-1 receptor (Cys94) and at position 190 in the SBDLII region of a mutant guinea pig sigma-1 receptor (C94A,V190C), both in a sigma-ligand (haloperidol or (+)-pentazocine)-sensitive manner. Significantly, photocross-linking followed by Endo Lys-C cleavage under reducing conditions and intramolecular radiolabel transfer from the SBDLI to the SBDLII region in the wild type receptor and, conversely, from the SBDLII to the SBDLI region in the mutant receptor were observed. These data support a model in which the SBDLI and SBDLII regions are juxtaposed to form, at least in part, a ligand binding site of the sigma-1 receptor. 相似文献
653.
Most drugs and xenobiotics induce the expression of cytochrome P450 (CYP) enzymes, which reduce the bioavailability of the inducer and/or co-administered drugs. Therefore, evaluation of new drug candidates for their effect on CYP expression is an essential step in drug development. The available methods for this purpose are expensive and not amenable to high-throughput screening. We developed a fluorescence-based in vivo assay using transgenic Caenorhabditis elegans worms that express the green fluorescent protein (GFP) under the control of various CYP promoters. Using this assay, we found striking similarities between the worm CYPs and their human orthologs in their response to treatment with various drugs. For example,the antibiotic rifampicin, one of the strongest inducers of the human gene CYP3A4, was the strongest inducer of the worm ortholog CYP13A7. Since worms can be easily grown in liquid medium in microtitre plates, the assay described in this paper is suitable for the screening of a large number of potential lead compounds in the drug discovery process. 相似文献
654.
Subramaniam D Natarajan G Ramalingam S Ramachandran I May R Queimado L Houchen CW Anant S 《American journal of physiology. Gastrointestinal and liver physiology》2008,294(4):G1025-G1032
CUGBP2, a translation inhibitor, induces colon cancer cells to undergo apoptosis. Mcl-1, an antiapoptotic Bcl-2 family protein, interferes with mitochondrial activation to inhibit apoptosis. Here, we have determined the effect of CUGBP2 on Mcl-1 expression. We developed a HCUG2 cell line by stably expressing CUGBP2 in the HCT-116 colon cancer cells. HCUG2 cells demonstrate decreased levels of proliferation and increased apoptosis, compared with HCT-116 cells. Flow cytometry analysis demonstrated higher levels of cells in the G(2)-M phase. Western blot analyses demonstrated that there was decreased Bcl-2 and Mcl-1 protein but increased expression of Bax, cyclin B1, and Cdc2. Immunocytochemistry also demonstrated increased levels of cyclin B1 and Cdc2 in the nucleus of HCUG2 cells. However, there was colocalization of phosphorylated histone H3 with transferase-mediated dUTP nick-end labeling (TUNEL). Furthermore, immunostaining for alpha-tubulin demonstrated that there was disorganization of microtubules. These data suggest that CUGBP2 expression in HCUG2 cells induces the cells to undergo apoptosis during the G(2)-M phase of the cell cycle. We next determined the mechanism of CUGBP2-mediated reduction in Mcl-1 expression. Mcl-1 protein, but not Mcl-1 mRNA, was lower in HCUG2 cells, suggesting translation inhibition. CUGBP2 binds to Mcl-1 3'-untranslated region (3'-UTR) both in vitro and in HCUG2 cells. Furthermore, CUGBP2 increased the stability of both endogenous Mcl-1 and luciferase mRNA containing the Mcl-1 3'-UTR. However, luciferase protein expression from the luciferase-Mcl-1 3'-UTR mRNA was suppressed. Taken together, these data demonstrate that CUGBP2 inhibits Mcl-1 expression by inhibiting Mcl-1 mRNA translation, resulting in driving the cells to apoptosis during the G(2) phase of the cell cycle. 相似文献
655.
Rai TS Dhandapany PS Ahluwalia TS Bhardwaj M Bahl A Talwar KK Nair K Rathinavel A Khullar M 《Molecular and cellular biochemistry》2008,311(1-2):67-72
Aim The study was carried to determine the association of angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism
with the risk of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM). Methods and results A total of 174 patients diagnosed with cardiomyopathy (118 with HCM, 51 with DCM, and 5 with RCM) and 164 ethnically, age-
and gender-matched controls were included in the study. ACE I/D genotyping was performed by PCR. In total, 25.86% of the patients
were in New York Heart Association (NYHA) class III and IV at presentation. A total of 67.24% patients had dyspnea, 56.89%
had angina pectoris, and 25.28% of the patients had at least one event of syncope. Frequency of occurrence of the disease
was more in male patients compared to female patients (P < 0.05). After adjustment for age, sex, body mass index (BMI), and smoking habit, the prevalence of ACE DD genotype, and
ACE ‘D’ allele was significantly higher in patients as compared to controls and was associated with increased risk (DD: OR
2.11, 95% CI 1.27–3.52, P < 0.05; ‘D’: OR 1.91, 95% CI 1.08–3.35, P < 0.05). The mean septal thickness was higher for DD and ID genotypes (20.40 ± 3.73 mm and 21.82 ± 5.35 mm, respectively)
when compared with II genotype (18.63 ± 6.69 mm) in HCM patients, however, the differences were not significant statistically
(P > 0.05). The DCM patients with ID genotype showed significantly decreased left ventricular ejection fraction (LVEF) at enrolment
(26.50 ± 8.04%) (P = 0.04). Conclusion Our results suggest that D allele of ACE I/D polymorphism significantly influences the HCM and DCM phenotypes. 相似文献
656.
Severson WE McDowell M Ananthan S Chung DH Rasmussen L Sosa MI White EL Noah J Jonsson CB 《Journal of biomolecular screening》2008,13(9):879-887
Using a highly reproducible and robust cell-based high-throughput screening (HTS) assay, the authors screened a 100,000-compound library at 14- and 114-microM compound concentration against influenza strain A/Udorn/72 (H3N2). The "hit" rates (>50% inhibition of the viral cytopathic effect) from the 14- and 114-microM screens were 0.022% and 0.38%, respectively. The hits were evaluated for their antiviral activity, cell toxicity, and selectivity in dose-response experiments. The screen at the lower concentration yielded 3 compounds, which displayed moderate activity (SI(50) = 10-49). Intriguingly, the screen at the higher concentration revealed several additional hits. Two of these hits were highly active with an SI(50) > 50. Time of addition experiments revealed 1 compound that inhibited early and 4 other compounds that inhibited late in the virus life cycle, suggesting they affect entry and replication, respectively. The active compounds represent several different classes of molecules such as carboxanilides, 1-benzoyl-3-arylthioureas, sulfonamides, and benzothiazinones, which have not been previously identified as having antiviral/anti-influenza activity. 相似文献
657.
Kalaimagal T Muthaiah A Rajarathinam S Malini S Nadarajan N Pechiammal I 《Journal of applied genetics》2008,49(3):221-227
Exploitation of hybrid vigour is quite possible in cross-pollinated crops. However, pigeonpea is a grain legume crop with a moderate level of cross-pollination (20-70%), which is mainly aided by insect pollinators. As a first step, hybrids based on genetic male sterility (GMS) were developed in pigeonpea, but the hybrid seed production technique is not farmer-friendly, because in the hybrid seed production plot 50% of the population, which are male-fertile in the female rows, have to be eliminated in time before contamination. This requires skilled labour and is a time-consuming process, which increases the cost of hybrid seed production. Therefore, the objective of this study was to develop cytoplasmic-genetic male-sterile (CGMS) lines in pigeonpea through wide hybridization, which would be very suitable for hybrid seed production. Two CGMS lines, viz. CORG 990052 A and CORG 990047, were developed by interspecific hybridization of Cajanus cajan and C. scarabaeoides. Restorers were identified and three CGMS-based pigeonpea hybrids were developed. The hybrid COPH 3 is found to be promising in Tamil Nadu State, India. 相似文献
658.
Josephine Hjoberg Stephanie Shore Lester Kobzik Shoji Okinaga Arlene Hallock Joseph Vallone Venkat Subramaniam George T De Sanctis Jack A Elias Jeffrey M Drazen Eric S Silverman 《Journal of applied physiology》2004,97(1):249-259
Individuals with asthma have increased levels of nitric oxide in their exhaled air. To explore its role, we have developed a regulatable transgenic mouse capable of overexpressing inducible nitric oxide synthase in a lung-specific fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse tetracycline transactivator under the control of the Clara cell protein promoter and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA-NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined to the airway epithelium. The fraction of expired nitric oxide increases over the first 24 h from approximately 10 parts per billion to a plateau of approximately 20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2 mice, with or without doxycycline, and wild-type mice in lung histology, bronchoalveolar protein, total cell count, or count differentials. However, airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10-rtTA-NOS-2 mice without doxycycline or wild-type mice with doxycycline. Moreover, doxycycline-treated CC10-rtTA-NOS-2 mice were hyporesponsive to methacholine compared with other groups. These data suggest that increased nitric oxide in the airways has no proinflammatory effects per se and may have beneficial effects on pulmonary function. 相似文献
659.
MOTIVATION: Extracting functional information from protein-protein interactions (PPI) poses significant challenges arising from the noisy, incomplete, generic and static nature of data obtained from high-throughput screening. Typical proteins are composed of multiple domains, often regarded as their primary functional and structural units. Motivated by these considerations, domain-domain interactions (DDI) for network-based analyses have received significant recent attention. This article performs a formal comparative investigation of the relationship between functional coherence and topological proximity in PPI and DDI networks. Our investigation provides the necessary basis for continued and focused investigation of DDIs as abstractions for functional characterization and modularization of networks. RESULTS: We investigate the problem of assessing the functional coherence of two biomolecules (or segments thereof) in a formal framework. We establish essential attributes of admissible measures of functional coherence, and demonstrate that existing, well-accepted measures are ill-suited to comparative analyses involving different entities (i.e. domains versus proteins). We propose a statistically motivated functional similarity measure that takes into account functional specificity as well as the distribution of functional attributes across entity groups to assess functional similarity in a statistically meaningful and biologically interpretable manner. Results on diverse data, including high-throughput and computationally predicted PPIs, as well as structural and computationally inferred DDIs for different organisms show that: (i) the relationship between functional similarity and network proximity is captured in a much more (biologically) intuitive manner by our measure, compared to existing measures and (ii) network proximity and functional similarity are significantly more correlated in DDI networks than in PPI networks, and that structurally determined DDIs provide better functional relevance as compared to computationally inferred DDIs. 相似文献
660.
With the exponential rise in the number of viable novel drug targets, computational methods are being increasingly applied to accelerate the drug discovery process. Virtual High Throughput Screening (vHTS) is one such established
methodology to identify drug candidates from large collection of compound libraries. Although it complements the expensive and time consuming High Throughput Screening (HTS) of compound libraries, vHTS possess inherent challenges.
The successful vHTS requires the careful implementation of each phase of computational screening experiment right from target preparation to hit identification and lead optimization. This article discusses some of the important
considerations that are imperative for designing a successful vHTS experiment. 相似文献