Comprehending the Structure, Dynamics, and Mechanism of Action of Drug-Resistant HIV Protease.

Since the emergence of the Human Immunodeficiency Virus (HIV) in the 1980s, strategies to combat HIV-AIDS are continuously evolving. Among the many tested targets to tackle this virus, its protease enzyme (PR) was proven to be an attractive option that brought about numerous research publications and ten FDA-approved drugs to inhibit the PR activity. However, the drug-induced mutations in the enzyme made these small molecule inhibitors ineffective with prolonged usage.

Structural basis for distinct operational modes and protease activation in AAA+ protease Lon.

Substrate-bound structures of AAA+ protein translocases reveal a conserved asymmetric spiral staircase architecture wherein a sequential ATP hydrolysis cycle drives hand-over-hand substrate translocation. However, this configuration is unlikely to represent the full conformational landscape of these enzymes, as biochemical studies suggest distinct conformational states depending on the presence or absence of substrate. Here, we used cryo-electron microscopy to determine structures of the Lon AAA+ protease in the absence and presence of substrate, uncovering the mechanistic basis for two distinct operational modes.

Aurora A site specific TACC3 phosphorylation regulates astral microtubule assembly by stabilizing γ-tubulin ring complex.

Background: Astral microtubules emanating from the mitotic centrosomes play pivotal roles in defining cell division axis and tissue morphogenesis. Previous studies have demonstrated that human transforming acidic coiled-coil 3 (TACC3), the most conserved TACC family protein, regulates formation of astral microtubules at centrosomes in vertebrate cells by affecting γ-tubulin ring complex (γ-TuRC) assembly. However, the molecular mechanisms underlying such function were not completely understood.