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991.
Kelly BN Kyere S Kinde I Tang C Howard BR Robinson H Sundquist WI Summers MF Hill CP 《Journal of molecular biology》2007,373(2):355-366
The CA domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein plays critical roles in both the early and late phases of viral replication and is therefore an attractive antiviral target. Compounds with antiviral activity were recently identified that bind to the N-terminal domain of CA (CAN) and inhibit capsid assembly during viral maturation. We have determined the structure of the complex between CAN and the antiviral assembly inhibitor N-(3-chloro-4-methylphenyl)-N′-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-methyl)-sulfanyl]ethyl}-urea) (CAP-1) using a combination of NMR spectroscopy and X-ray crystallography. The protein undergoes a remarkable conformational change upon CAP-1 binding, in which Phe32 is displaced from its buried position in the protein core to open a deep hydrophobic cavity that serves as the ligand binding site. The aromatic ring of CAP-1 inserts into the cavity, with the urea NH groups forming hydrogen bonds with the backbone oxygen of Val59 and the dimethylamonium group interacting with the side-chains of Glu28 and Glu29. Elements that could be exploited to improve binding affinity are apparent in the structure. The displacement of Phe32 by CAP-1 appears to be facilitated by a strained main-chain conformation, which suggests a potential role for a Phe32 conformational switch during normal capsid assembly. 相似文献
992.
The crystal structure of mouse Exo70 reveals unique features of the mammalian exocyst 总被引:6,自引:0,他引:6
The exocyst is a eukaryotic tethering complex necessary for the fusion of exocytic vesicles with the plasma membrane. Its function in vivo is tightly regulated by interactions with multiple small GTPases. Exo70, one of the eight subunits of the exocyst, is important for the localization of the exocyst to the plasma membrane. It interacts with TC10 and Rho3 GTPases in mammals and yeast, respectively, and has been shown recently to bind to the actin-polymerization complex Arp2/3. Here, we present the crystal structure of Mus musculus Exo70 at 2.25 A resolution. Exo70 is composed of alpha-helices in a series of right-handed helix-turn-helix motifs organized into a long rod of length 170 A and width 35 A. Although the alpha-helical organization of this molecule is similar to that in Saccharomyces cerevisiae Exo70, major structural differences are observed on the surface of the molecule, at the domain boundaries, and in various loop structures. In particular, the C-terminal domain of M. musculus Exo70 adopts a new orientation relative to the N-terminal half not seen in S. cerevisiae Exo70 structures. Given the low level of sequence conservation within Exo70, this structure provides new insights into our understanding of many species-specific functions of the exocyst. 相似文献
993.
Johnson AR Pavlovsky AG Ortwine DF Prior F Man CF Bornemeier DA Banotai CA Mueller WT McConnell P Yan C Baragi V Lesch C Roark WH Wilson M Datta K Guzman R Han HK Dyer RD 《The Journal of biological chemistry》2007,282(38):27781-27791
Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients. 相似文献
994.
Hang H 《The Journal of cell biology》2007,178(3):340-341
Howard Hang is cutting through the forest of posttranslational modifications in an attempt to better understand how human pathogens alter this terrain. 相似文献
995.
Peripheral administration of the endogenous Y(2) and Y(4) receptor selective agonists, PYY(3-36) and PP, have been shown to inhibit food intake and body weight gain in rodents, and to reduce appetite and caloric intake in humans. We have previously developed a long-acting, potent and highly selective Y(2) receptor selective agonist, N-alpha-Ac-[Nle(24,28), Trp(30), Nva(31), Psi(35-36)]PYY(22-36)-NH(2) (BT-48). BT-48 (ip) dose-dependently inhibited ad lib food intake and also decreased the respiratory quotient in mice during both the light and dark periods. The latter observation is indicative of enhanced fat metabolism. Moreover, BT-48 also inhibited food intake in fasted mice. Combined ip administration of BT-48 (50nmol/mouse) with a highly potent and selective Y(4) anorectic peptide, BVD-74D (50nmol/mouse), resulted in a powerful and long lasting inhibitory effect on food intake. As expected, this inhibitory effect on food intake was nearly double that exhibited by either peptide (50nmol/mouse) alone. In summary, BT-48, unlike PYY(3-36), exhibits little or no affinity to other "Y" receptors, and may therefore have a better clinical potential than PYY(3-36) for control of food intake. Moreover, it appears that treatment with a combination of Y(2) and Y(4) receptor selective agonists may constitute a more powerful approach to control food intake than treatment with either of these agonists alone. 相似文献
996.
997.
Slovin SF Ragupathi G Fernandez C Diani M Jefferson MP Wilton A Kelly WK Morris M Solit D Clausen H Livingston P Scher HI 《Cancer immunology, immunotherapy : CII》2007,56(12):1921-1930
We have shown the immunogenicity and safety of synthetic carbohydrate vaccines when conjugated to the carrier keyhole limpet
hemocyanin (KLH) and given with the adjuvant, QS-21, in patients with biochemically relapsed prostate cancer. To determine
whether immune response could be further enhanced with stimulation by multiple antigens, a hexavalent vaccine was prepared
using previously determined doses and administered in a Phase II setting to 30 high-risk patients. The hexavalent vaccine
included GM2, Globo H, Lewisy, glycosylated MUC-1-32mer and Tn and TF in a clustered formation, conjugated to KLH and mixed with QS-21. Eight vaccinations
were administered over 13 months. All 30 patients had significant elevations in antibody titers to at least two of the six
antigens; 22 patients had increased reactivity with FACS. These serologic responses were lower than that seen previously in
patients treated with the respective monovalent vaccines. The reciprocal median combined IgM and IgG antibody titers with
ELISA against MUC1, Tn, TF, globo H and GM2 for these 30 patients were 640, 80, 120, 40 and 0, compared to 1280, 640, 1280,
320 and 160 seen in patients receiving individual monovalent vaccines. This hexavalent vaccine of synthetic “self” antigens
broke immunologic tolerance against two or more antigens in all 30 vaccinated patients, was safe, but antibody titers against
several of the antigens were lower than those seen in individual monovalent trials. No impact on PSA slope was detected. We
address the relevance of the multivalent approach for prostate cancer treatment.
Supported by the Prostate Cancer Foundation, The PepsiCo Foundation, The Sharon Hels and Brad Reed Fund, Swim Across America,
The Sara Chait Foundation.
Dr. Philip Livingston is a consultant for and shareholder in Progenics Pharmaceuticals, Inc. 相似文献
998.
Pregnancy and lactation are states known to be accompanied by physiologically up regulated bone resorption in response to the calcium demands of the developing fetus and nursing infant. The role of calcium supplements in altering maternal responses to fetal demand for calcium is not fully understood. Exposure to the toxicant lead is known to pose a major hazard to fetal neurodevelopment and growth. Since >95% of maternal lead is stored in the bone, mobilization of cumulative maternal lead stores into the circulation represents an endogenous source of exposure, which may pose a significant hazard for the fetus and infant. Maternal dietary calcium supplementation has been associated with reductions in lead levels in both animal and human studies when administered during pregnancy and lactation. Therefore, supplementation of the maternal diet with calcium may represent an important secondary prevention strategy aimed not only at reducing circulating levels of lead in the mother but also at reducing lead exposure to the developing fetus and nursing infant. 相似文献
999.
1000.