Trimer

About: Trimer is a research topic. Over the lifetime, 4756 publications have been published within this topic receiving 111761 citations.

Crystal structure of a soluble cleaved HIV-1 envelope trimer.

Abstract: HIV-1 entry into CD4+ target cells is mediated by cleaved envelope glycoprotein (Env) trimers that have been challenging to characterize structurally. Here, we describe the crystal structure at 4.7 A of an antigenically near-native, cleaved, stabilized, soluble Env trimer (termed BG505 SOSIP.664 gp140) in complex with a potent broadly neutralizing antibody, PGT122. The structure shows a pre-fusion state of gp41, the interaction between the component gp120 and gp41 subunits, and how a close association between the gp120 V1/V2/V3 loops stabilizes the trimer apex around the three-fold axis. The complete epitope of PGT122 on the trimer involves gp120 V1, V3 and several surrounding glycans. This trimer structure advances our understanding of how Env functions and is presented to the immune system, and provides a blueprint for structure-based vaccine design.

Molecular architecture of native HIV-1 gp120 trimers.

Abstract: The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.

pppA2'p5'A2'p5'A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells

Abstract: A low molecular weight inhibitor of cell-free protein synthesis effective at subnanomolar concentrations is formed on incubation of cytoplasmic extracts from interferon-treated cells with double-stranded RNA and ATP. It can be conveniently synthesized by incubating a poly(I).poly(C)-Sepharose-bound enzyme fraction from such cells with [3H]- or [alpha- or gamma-32P]ATP. The radioactive inhibitor has been characterized by its behavior on DEAE-Sephadex in the presence of urea and on the basis of the products obtained on enzymic, alkaline, and sequential degradation by periodate oxidation and beta elimination. Its structure appears to be pppA2'p5'A2'p5'A. We have found no evidence for any modification or abnormality other than the 2'-5' linkage. On occasion the inhibitor preparations have included what seems to be the corresponding dimer (pppA2'p5'A), tetramer [ppp(A2'p)3A], pentamer [ppp(A2'p)4A], and higher oligomers in decreasing amounts. The trimer, tetramer, and pentamer are similar in activity, but the dimer is less potent if active at all.

Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer

Abstract: The HIV-1 envelope glycoprotein (Env) trimer contains the receptor binding sites and membrane fusion machinery that introduce the viral genome into the host cell. As the only target for broadly neutralizing antibodies (bnAbs), Env is a focus for rational vaccine design. We present a cryo-electron microscopy reconstruction and structural model of a cleaved, soluble SOSIP gp140 trimer in complex with a CD4 binding site (CD4bs) bnAb, PGV04, at 5.8 A resolution. The structure reveals the spatial arrangement of Env components, including the V1/V2, V3, HR1 and HR2 domains, and shielding glycans. The structure also provides insights into trimer assembly, gp120-gp41 interactions, and the CD4bs epitope cluster for bnAbs, which covers a more extensive area and defines a more complex site of vulnerability than previously described.

Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids.

Abstract: Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.