Structural and functional characterization of the human CCR5 receptor in complex with HIV gp120 envelope glycoprotein and CD4 receptor by molecular modeling studies

The entry of human immunodeficiency virus (HIV) into cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors CD4 and members of the chemokine receptor family. The CC chemokine receptor CCR5 is such a receptor for several chemokines and a major coreceptor for the entry of R5 HIV type-1 (HIV-1) into cells. Although many studies focus on the interaction of CCR5 with HIV-1, the corresponding interaction sites in CCR5 and gp120 have not been matched. Here we used an approach combining protein structure modeling, docking and molecular dynamics simulation to build a series of structural models of the CCR5 in complexes with gp120 and CD4. Interactions such as hydrogen bonds, salt bridges and van der Waals contacts between CCR5 and gp120 were investigated. Three snapshots of CCR5-gp120-CD4 models revealed that the initial interactions of CCR5 with gp120 are involved in the negatively charged N-terminus (Nt) region of CCR5 and positively charged bridging sheet region of gp120. Further interactions occurred between extracellular loop2 (ECL2) of CCR5 and the base of V3 loop regions of gp120. These interactions may induce the conformational changes in gp120 and lead to the final entry of HIV into the cell. These results not only strongly support the two-step gp120-CCR5 binding mechanism, but also rationalize extensive biological data about the role of CCR5 in HIV-1 gp120 binding and entry, and may guide efforts to design novel inhibitors.

甘肃西峰黄土剖面500 ka以来的蜗牛化石记录及其古气候、古环境变化研究

The loess-paleosol sequences in China are among the best continental records of paleoclimate changes. Although numerous sedimentological and geochemical studies have contributed greatly to the understanding of past climate changes during this period, it is still necessary to decipher more details through investigating these sequences using various approaches including biological analyses. In this study, we analyze the mollusk fossil assemblages preserved in the upper part of the Xifeng section, from the fifth loess layer (L5) to the Holocene soil (S0), with the sampling interval of 10 cm. The main results and conclusions obtained are as follows: 1. A continuous terrestrial mollusk fossil record, covering the past 500 ka, has been obtained from the Xifeng loess-paleosol sequence, which provides important biological data for the study of paleoenvironmental changes in the Loess Plateau and its comparison with marine record during this period. A total of 475 mollusk assemblages were studied, and twenty-one species have been identified among the 210,000 mollusk individuals counted. Among these species, most have modern representatives and are found in previous terrestrial mollusk studies of Chinese loess-paleosol sequences. Thus, they can be grouped into cold-aridiphilous, thermo-humidiphilous, oriental, and cool-humidiphilous ecological groups, as defined by previous studies. 2. Comparison of mollusk assemblages between the last five glacials and four interglacials and Holocene shows very different climate conditions. The warmest period occurred at MIS 11, MIS 5e, and Holocene, respectively. The coldest period is the Last Glacial Maximam, rather than the MIS 12. 3. Our mollusk record provides insight into the climate conditions in the Loess Plateau during the MIS 11, interpreted as the closest analog to the present interglacial. S4 paleosol, equivalent of MIS 11, developed under two major different climate regimes: ranging from the very warm–humid early phase to the mild-cool late interval. Furthermore, a cooling spell has been documented at the interglacial optimum, reflecting unstable climate conditions. The early warm–humid conditions lasted over 30 ka, supporting that MIS 11 is a unique long interglacial in the Quaternary climate history. 4. Comparison of MIS 11 and Holocene climates based on the mollusk species compositions indicates major differences. The climate at the early part of MIS 11 was warmer and more humid than during the Holocene optimum period, but the conditions during the late part of MIS 11 were similar to or cooler than late Holocene. Our study indicates that the extent of warming during the Holocene might be significantly less than the conditions that prevailed during the early part of MIS 11 interglacial period. 5. Two strong summer monsoon events were observed during the MIS 12 and MIS 10. They correspond to the maximam values of insolation gradient between low and high latitudes, suggesting a causal linkage. 6. Our study, combined with the previously investigated Luochuan land snail record, reveals that the climate in the Loess Plateau during MIS 3 experienced three stages: relatively warm, humid climate prevailed during MIS 3c, relatively cold, dry climate during MIS 3b, and relatively warm-humid period during MIS 3a. Climate at this time fluctuated frequently in Luochuan, and changed from warm-cool to cold-dry in Xifeng. Our results reveal that the relatively warm-humid climate during MIS 3c may be resulted from an increasing insolation gradient controlled by obliquity. Our result also reveals that obvious regional difference existed in the Loess Plateau during MIS 3. A greater climate gradient occurred during this time compared with today’s climate pattern in the Loess Plateau.

Uncovering the rules for protein-protein interactions from yeast genomic data

Identifying protein-protein interactions is crucial for understanding cellular functions. Genomic data provides opportunities and challenges in identifying these interactions. We uncover the rules for predicting protein-protein interactions using a frequent pattern tree (FPT) approach modified to generate a minimum set of rules (mFPT), with rule attributes constructed from the interaction features of the yeast genomic data. The mFPT prediction accuracy is benchmarked against other commonly used methods such as Bayesian networks and logistic regressions under various statistical measures. Our study indicates that mFPT outranks other methods in predicting the protein-protein interactions for the database used. We predict a new protein-protein interaction complex whose biological function is related to premRNA splicing and new protein-protein interactions within existing complexes based on the rules generated.