Ras S89D mutation induced allosteric changes that promoted its nucleotide exchange and signaling activation.

The small GTPase Ras is among the most frequently mutated genes and its mutations often drive oncogenesis across various cancers. While the role of NRas phosphorylation at S89 in the context of a Q61R mutation in melanoma genesis remains controversial, the impact of S89 phosphorylation on NRas function has not been fully elucidated. In this study, we employed the S89D phosphorylation-mimetic mutation and demonstrated that the S89D mutation alone activated all Ras isoforms by increasing the GTP-bound population, thereby promoting ERK phosphorylation and cell proliferation.

The cellular and molecular targets of natural products against metabolic disorders: a translational approach to reach the bedside.

Metabolic disorders, including obesity, dyslipidemia, diabetes, nonalcoholic fatty liver disease, and metabolic syndrome, are characterized by insulin resistance, abnormalities in circulating cholesterol and lipid profiles, and hypertension. The most common pathophysiologies of metabolic disorders are glucose/lipid metabolism dysregulation, insulin resistance, inflammatory response, and oxidative stress. Although several agents have been approved for the treatment of metabolic disorders, there is still a strong demand for more efficacious drugs with less side effects.

Patients' needs and experiences of telerehabilitation after total hip and knee arthroplasty: A qualitative systematic review and meta-synthesis.

Background: The number of patients undergoing joint replacement procedures is continuously increasing. Tele-equipment is progressively being employed for postrehabilitation of total hip and knee replacements. Gaining a comprehensive understanding of the experiences and requirements of patients undergoing total hip and knee arthroplasty who participate in telerehabilitation can contribute to the enhancement of telerehabilitation programs and the overall rehabilitation and care provided to this specific population.

Patient Self-Management Scale After Total Knee Arthroplasty (PSMS-TKA): Instrument Development and Cross-Sectional Validation Study.

Background: Effective self-management after total knee arthroplasty (TKA) not only improves patients' knee pain and physical function but also improves quality of life. However, there is no assessment tool that can be targeted to evaluate the self-management level of patients after TKA. This study aimed to develop and validate a scale to specifically assess the level of self-management in patients after TKA.

The Needs and Experiences of Patients Returning to Work After Total Knee Arthroplasty and Total Hip Arthroplasty: A Systematic Review and Meta-Synthesis.

Objective: The objective of this study was to conduct a systematic and comprehensive review of qualitative research to examine the physical and psychological needs, as well as work experiences, of patients undergoing total knee replacement and total hip replacement surgeries during their process of returning to work.

Methods: A systematic review and meta-synthesis of qualitative literature was conducted. A systematic search was conducted across 8 databases to identify qualitative or mixed-methods research on the needs and experiences of individuals with total knee replacement and total hip replacement who have returned to work.

STK19 is a DNA/RNA-binding protein critical for DNA damage repair and cell proliferation.

STK19 was originally identified as a manganese-dependent serine/threonine-specific protein kinase, but its function has been highly debated. Here, the crystal structure of STK19 revealed that it does not contain a kinase domain, but three intimately packed winged helix (WH) domains. The third WH domain mediated homodimerization and double-stranded DNA binding, both being important for its nuclear localization.

Nuclear transport proteins: structure, function, and disease relevance.

Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport is a fundamental cellular process that regulates the localization of many macromolecules within the nuclear or cytoplasmic compartments. In humans, approximately 60 proteins are involved in nuclear transport, including nucleoporins that form membrane-embedded nuclear pore complexes, karyopherins that transport cargoes through these complexes, and Ran system proteins that ensure directed and rapid transport.

Discovery and Optimization of Novel DHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (DHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1-pyrazolo[3,4-]pyridine scaffold was identified as an DHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1-pyrrolo[2,3-]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (, which was found to be the most promising and drug-like compound with potent inhibitory activity against DHODH (IC = 173.

Discovery of Aminoratjadone Derivatives as Potent Noncovalent CRM1 Inhibitors.

Cancer cells frequently utilize elevated nuclear export to escape tumor suppression and gain proliferative advantage. Chromosome Region Maintenance 1 (CRM1/XPO1) mediates macromolecule nuclear export and plays an important role in tumorigenesis and progression. The clinical approval of its covalent inhibitor KPT-330 (Selinexor) validates the feasibility of targeting CRM1 to treat cancers.

Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B.

Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival.

Cryo-EM structure of the Mon1-Ccz1-RMC1 complex reveals molecular basis of metazoan RAB7A activation.

Understanding of the evolution of metazoans from their unicellular ancestors is a fundamental question in biology. In contrast to fungi which utilize the Mon1-Ccz1 dimeric complex to activate the small GTPase RAB7A, metazoans rely on the Mon1-Ccz1-RMC1 trimeric complex. Here, we report a near-atomic resolution cryogenic-electron microscopy structure of the Mon1-Ccz1-RMC1 complex.

Structure-Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against .

Discovery of novel antitubercular drugs is an effective strategy against drug-resistant tuberculosis (TB). Our previous study has identified as a novel antitubercular compound. Herein, we perform a comprehensive structure-activity relationship (SAR) based on , indicating that the central pyrimidine ring moiety was crucial for the antitubercular activities of its derivatives, and replacing the naphthyl group with hydrophobic substitutes was well tolerated.

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach.

Chromosomal region maintenance protein 1 (CRM1) is a validated anticancer drug target, and its covalent inhibitor KPT-330 has been approved for marketing. However, the development of CRM1 inhibitors, especially the noncovalent ones, is still very limited. Drug repurposing is an effective strategy to develop drug leads for new targets.

Application of a deep generative model produces novel and diverse functional peptides against microbial resistance.

Antimicrobial resistance could threaten millions of lives in the immediate future. Antimicrobial peptides (AMPs) are an alternative to conventional antibiotics practice against infectious diseases. Despite the potential contribution of AMPs to the antibiotic's world, their development and optimization have encountered serious challenges.

Discovery and Mechanistic Study of PafA Inhibitors.

Tuberculosis is caused by the bacterium () and is ranked as the second killer infectious disease after COVID-19. Proteasome accessory factor A (PafA) is considered an attractive target because of its low sequence conservation in humans and its role in virulence. In this study, we designed a mutant of PafA that enabled large-scale purification of active PafA.

Identification of selective mtbDHFR inhibitors by virtual screening and experimental approaches.

mtbDHFR-targeting inhibition has become a promising approach for tuberculosis treatment. In the current research, a multi-step virtual screening effort toward ZINC and MCE databases was devoted to discover novel mtbDHFR inhibitors. Based on binding affinity of small molecules through molecular docking study in AutoDock Vina, the number of compounds was reduced to 952,688.

Biophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors.

The rate-limiting serine biogenesis enzyme PHGDH is overexpressed in cancers. Both serine withdrawal and genetic/pharmacological inhibition of PHGDH have demonstrated promising tumor-suppressing activities. However, the enzyme properties of PHGDH are not well understood and the discovery of PHGDH inhibitors is still in its infancy.

Nuclear import receptors and hnRNPK mediates nuclear import and stress granule localization of SIRLOIN.

The majority of lncRNAs and a small fraction of mRNAs localize in the cell nucleus to exert their functions. A SIRLOIN RNA motif was previously reported to drive its nuclear localization by the RNA-binding protein hnRNPK. However, the underlying mechanism remains unclear.

Chromosome Region Maintenance 1 (XPO1/CRM1) as an Anticancer Target and Discovery of Its Inhibitor.

Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor protein and contributes to cell homeostasis by mediating the transport of cargo from the nucleus to the cytoplasm. CRM1 is a therapeutic target comprised of several tumor types, including osteosarcoma, multiple myeloma, gliomas, and pancreatic cancer. In the past decade, dozens of CRM1 inhibitors have been discovered and developed, including KPT-330, which received FDA approval for multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) in 2019 and 2020, respectively.

SNX27-FERM-SNX1 complex structure rationalizes divergent trafficking pathways by SNX17 and SNX27.

The molecular events that determine the recycling versus degradation fates of internalized membrane proteins remain poorly understood. Two of the three members of the SNX-FERM family, SNX17 and SNX31, utilize their FERM domain to mediate endocytic trafficking of cargo proteins harboring the NPxY/NxxY motif. In contrast, SNX27 does not recycle NPxY/NxxY-containing cargo but instead recycles cargo containing PDZ-binding motifs via its PDZ domain.

Discovery of novel inhibitors of human phosphoglycerate dehydrogenase by activity-directed combinatorial chemical synthesis strategy.

Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay.