The SMN complex mediates the assembly of heptameric Sm protein rings on small nuclear RNAs (snRNAs), which are essential for snRNP function. Specific Sm core assembly depends on Sm proteins and snRNA recognition by SMN/Gemin2- and Gemin5-containing subunits, respectively. The mechanism by which the Sm proteins are gathered while preventing illicit Sm assembly on non-snRNAs is unknown. Here, we describe the 2.5 Å crystal structure of Gemin2 bound to SmD1/D2/F/E/G pentamer and SMN's Gemin2-binding domain, a key assembly intermediate. Remarkably, through its extended conformation, Gemin2 wraps around the crescent-shaped pentamer, interacting with all five Sm proteins, and gripping its bottom and top sides and outer perimeter. Gemin2 reaches into the RNA-binding pocket, preventing RNA binding. Interestingly, SMN-Gemin2 interaction is abrogated by a spinal muscular atrophy (SMA)-causing mutation in an SMN helix that mediates Gemin2 binding. These findings provide insight into SMN complex assembly and specificity, linking snRNP biogenesis and SMA pathogenesis.
Mechanical metamaterials are architected manmade materials that allow for unique behaviors not observed in nature, making them promising candidates for a wide range of applications. Existing metamaterials lack tunability as their properties can only be changed to a limited extent after the fabrication. Herein, a new magneto-mechanical metamaterial is presented that allows great tunability through a novel concept of deformation mode branching. The architecture of this new metamaterial employs an asymmetric joint design using hard-magnetic soft active materials that permits two distinct actuation modes (bending and folding) under opposite-direction magnetic fields. The subsequent application of mechanical compression leads to the deformation mode branching where the metamaterial architecture transforms into two distinctly different shapes, which exhibit very different deformations and enable great tunability in properties such as mechanical stiffness and acoustic bandgaps. Furthermore, this metamaterial design can be incorporated with magnetic shape memory polymers with global stiffness tunability, which also allows for the global shift of the acoustic behaviors. The combination of magnetic and mechanical actuations, as well as shape memory effects, impart wide tunable properties to a new paradigm of metamaterials.
Magnetic soft materials (MSMs) have shown potential in soft robotics, actuators, metamaterials, and biomedical devices because they are capable of untethered, fast, and reversible shape reconfigurations as well as controllable dynamic motions under applied magnetic fields. Recently, magnetic shape memory polymers (M-SMPs) that incorporate hard magnetic particles in shape memory polymers demonstrated superior shape manipulation performance by realizing reprogrammable, untethered, fast, and reversible shape transformation and shape locking in one material system. In this work, we develop a multimaterial printing technology for the complex structural integration of MSMs and M-SMPs to explore their enhanced multimodal shape transformation and tunable properties. By cooperative thermal and magnetic actuation, we demonstrate multiple deformation modes with distinct shape configurations, which further enable active metamaterials with tunable physical properties such as sign-change Poisson's ratio. Because of the multiphysics response of the M-MSP/MSM metamaterials, one distinct feature is their capability of shifting between various global mechanical behaviors such as expansion, contraction, shear, and bending. We anticipate that the multimaterial printing technique opens new avenues for the fabrication of multifunctional magnetic materials.
Magnetic-responsive composites that consist of soft matrix embedded with hard-magnetic particles have recently been demonstrated as robust soft active materials for fast-transforming actuation. However, the deformation of the functional components commonly attains only a single actuation mode under external stimuli, which limits their capability of achieving tunable properties.To greatly enhance the versatility of soft active materials, we exploit a new class of programmable magnetic-responsive composites incorporated with a multifunctional joint design that allows asymmetric multimodal actuation under an external stimulation. We demonstrate that the proposed asymmetric multimodal actuation enables a plethora of novel applications ranging from the basic 1D/2D active structures with asymmetric shape-shifting to biomimetic crawling and swimming robots with efficient dynamic performance as well as 2D metamaterials with tunable properties.This new asymmetric multimodal actuation mechanism will open new avenues for the design of next-generation multifunctional soft robots, biomedical devices, and acoustic metamaterials.
In this study, the sensitivity of the CB2 receptor to methanethiosulfonate (MTS) derivatives was tested, and a native cysteine residue conferring the sensitivity was identified. By incubating human embryonic kidney 293 cells stably transfected with CB2 receptors and MTS derivatives such as MTS ethylammonium (MTSEA), [ ) for the MTSEA reaction with wild-type CB2 suggests that C2.59(89) resides at the margin of the CB2 binding site crevice. The accessibility of C2.59(89) to MTSEA provides experimental evidence for a possible conformational difference between TMH2 of CB2 versus Rho. Modeling studies undertaken to explore the origin of such differences suggest it is possibly caused by the conformational influence of S2.54(84).
Antibody-drug conjugates (ADCs) have achieved great success in cancer therapy in recent years. Some peptidyl microtubule inhibitors consisting of natural and unnatural amino acids, such as monomethyl auristatin E (MMAE) and F (MMAF), are extremely cytotoxic and have been used as a payload in ADCs.However, their precise molecular interaction with tubulin and microtubules remains unclear. We determined the crystal structures of tubulin in complex with three ultra-potent peptidyl microtubule inhibitors [MMAE,, and tubulysin M] at 2.5 Å. Our data showed that the three peptides bound to the vinca domain and shared a common and key pharmacophore containing two consecutive hydrophobic groups (Val, Ile-like side chain). These groups protruded in opposite directions into hydrophobic pockets on the tubulin b and a subunits. Nitrogen and oxygen atoms from the same backbone formed hydrogen bonds with Asn329 from the a subunit and Asp179 from the b subunit in a direction normal to the surface formed by the aforementioned hydrophobic groups. In addition, our crystal structure data indicated that tubulysin M bound to the b subunit alone, providing a structural explanation for its higher affinity. We also compared the conformations of two representative structurally different vinca domain compounds, ustiloxin D and vinblastine, with those of the aforementioned peptidyl ligands, and found that they shared a similar pharmacophore. Our findings lay a foundation for the rational design of novel vinca domain ligands and may facilitate the development of microtubule inhibitors with high specificity, affinity, and efficiency as payloads for ADCs in cancer therapy.
The potential for infection by coronaviruses (CoVs) has become a serious concern with the recent emergence of Middle East respiratory syndrome and severe acute respiratory syndrome (SARS) in the human population. CoVs encode two large polyproteins, which are then processed into 15-16 nonstructural proteins (nsps) that make significant contributions to viral replication and transcription by assembling the RNA replicase complex. Among them, nsp9 plays an essential role in viral replication by forming a homodimer that binds single-stranded RNA. Thus, disrupting nsp9 dimerization is a potential anti-CoV therapy. However, different nsp9 dimer forms have been reported for alpha- and beta-CoVs, and no structural information is available for gamma-CoVs. Here we determined the crystal structure of nsp9 from the avian infectious bronchitis virus (IBV), a representative gamma-CoV that affects the economy of the poultry industry because it can infect domestic fowl. IBV nsp9 forms a homodimer via interactions across a hydrophobic interface, which consists of two parallel alpha helices near the carboxy terminus of the protein. The IBV nsp9 dimer resembles that of SARS-CoV nsp9, indicating that this type of dimerization is conserved among all CoVs. This makes disruption of the dimeric interface an excellent strategy for developing anti-CoV therapies. To facilitate this effort, we characterized the roles of six conserved residues on this interface using site-directed mutagenesis and a multitude of biochemical and biophysical methods. We found that three residues are critical for nsp9 dimerization and its abitlity to bind RNA.
MIG (monokine induced by interferon-g) is a CXC chemokine ligand (CXCL9) that can potently inhibit angiogenesis, and displays thymus-dependent antitumor effects. The effectiveness of a treatment combining gene therapy with plasmid-borne MIG (pORF-MIG) and low-dose cisplatin chemotherapy was determined using colon carcinoma (CT26) and Lewis lung carcinoma (LL/2c) murine models. The program was carried out via intramuscular delivery of pORF-MIG at 100 mg/mouse twice a week for 4 weeks, and/or intraperitoneal delivery of cisplatin at 0.6 mg/kg/ mouse every 3 days for 48 days. Tumor volume and survival time were evaluated after treatment. CD31 immunohistochemical staining in tumor tissues and alginate capsule models in vivo was used to evaluate angiogenesis. Induction of apoptosis and cytotoxic T-lymphocyte (CTL) activity were also assessed. The combination of pORF-MIG and low-dose cisplatin produced significant antitumor activity, with complete tumor regression in 4/10 of CT26 colon carcinomas and 3/10 of LL/2c lung carcinomas, low vascularity, in alginate capsules, apparently degraded tumor microvessel density, and increased induction of apoptotic and CTL activities compared with either treatment alone. This study suggests that the combination of pORF-MIG plus cisplatin augments the inhibition of angiogenesis and the induction of apoptosis or CTL activity, all of which enhance antitumor activity. These findings may prove useful in further explorations of the application of combinatorial approaches to the treatment of solid tumors.
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