Others

Protein kinases (PK)

Protein kinases (PK) are a class of enzymes that catalyze the process of protein phosphorylation【1】. Within cells, protein kinases regulate protein activity through phosphorylation【2】, thereby participating in various biological processes such as cell signaling, cell proliferation, differentiation, and apoptosis. LRRK2 is a protein kinase. It belongs to the protein kinase family and is a multi-domain protein consisting of 2,527 amino acids, playing a fundamental role in controlling and regulating complex cellular processes. Additionally, mutations in LRRK2 are considered a primary cause of hereditary Parkinson's disease【3】, although scientists do not yet fully understand the function of this enzyme under normal or pathological conditions.

RNA

SARS-CoV-2 nsp12/7/8/RNA/AT-9010 Complex: The guanosine analog AT-527 is a promising candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once AT-527 enters cells, it is converted into its triphosphate form, AT-9010, which presumably targets the viral RNA-dependent RNA polymerase (RdRp, nsp12) and is incorporated into viral RNA. This study reports a 3.0 Å cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-nsp8-RNA complex, revealing AT-9010 bound at three sites of nsp12. In the RdRp active site, one AT-9010 is incorporated at the 3′ end of the RNA product strand. Its modified ribose group (2′-fluoro, 2′-methyl) prevents correct alignment of the incoming NTP (in this case, a second AT-9010), causing immediate termination of RNA synthesis. The third AT-9010 binds to the N-terminal domain of nsp12, known as the NiRAN domain. Unlike native NTPs, AT-9010 adopts a flipped orientation in the active site, with its guanine base unexpectedly occupying a previously unnoticed cavity. AT-9010 outcompetes all native nucleotides for binding to NiRAN, thereby inhibiting its nucleotidyltransferase activity. The dual mechanism of action of AT-527 — targeting both the RdRp and NiRAN active sites — represents a promising avenue for combating COVID-19【4】.

AAA ATPase Family

A broad class of proteins involved in diverse cellular activities. They participate not only in cell cycle regulation, proteolysis, and disaggregation, but also play crucial roles in processes such as organelle biogenesis and intracellular trafficking. These proteins may function as molecular chaperones, subunits of proteolytic complexes, or independent proteases, while also serving as DNA helicases and transcription factors【5】. Structurally, AAA ATPases exhibit a unique architecture, where they oligomerize (typically into hexamers) to form a ring - shaped complex with a central pore【6】. This assembly couples ATP binding and hydrolysis to conformational changes that enable substrate translocation or remodeling. These proteins are ubiquitously present across all organisms and share a conserved AAA domain, known as the AAA module. Biomedical Significance: The AAA ATPase family plays a vital role in the initiation and progression of malignancies【7】. Dysregulated function or mutations in these proteins are closely associated with tumorigenesis and cancer aggressiveness. For instance, the AAA+ protein family member hCDC48/p97 (VCP) exhibits significantly elevated expression in multiple malignancies and contributes to tumor cell proliferation and pathological invasion. Additionally, ATP6AP2 (also known as Ac45, a proton pump regulator) shows upregulated expression in various cancers, including breast cancer, gastrointestinal tumors, lung cancer, and pancreatic cancer【7】.