Nature chemical biology最新文献

Biomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the three-dimensional (3D) structure, the lifetime of a ground conformational state determines its biological activity. Using hydrogen–deuterium exchange nuclear magnetic resonance spectroscopy, we found that Zika virus exoribonuclease-resistant RNA (xrRNA) encodes a ground conformational state with a lifetime that is ~10⁵–10⁷ longer than that of canonical base pairs. Mutations that shorten the apparent lifetime of the ground state without affecting its 3D structure decreased exoribonuclease resistance in vitro and impaired virus replication in cells. Additionally, we observed this exceptionally long-lived ground state in xrRNAs from diverse infectious mosquito-borne flaviviruses. These results demonstrate the biological importance of the lifetime of a preorganized ground state and further suggest that elucidating the lifetimes of dominant 3D structures of biomolecules may be crucial for understanding their behaviors and functions.

Measuring pharmacodynamics (PD)—the biochemical effects of drug dosing—and correlating them with therapeutic efficacy in animal models is crucial for the development of effective drugs but traditional PD studies are labor and resource intensive. Here we developed a kinase-modulated bioluminescent indicator (KiMBI) for rapid, noninvasive PD assessment of Akt-targeted drugs, minimizing drug and animal use. Using KiMBI, we performed a structure–PD relationship analysis on the brain-active Akt inhibitor ipatasertib by generating and characterizing two novel analogs. One analog, ML-B01, successfully inhibited Akt in both the brain and the body. Interestingly, capivasertib, ipatasertib and ML-B01 all exhibited PD durations beyond their pharmacokinetic profiles. Furthermore, KiMBI revealed that the PD effects of an Akt-targeted proteolysis-targeting chimera degrader endured for over 3 days. Thus, bioluminescence imaging with Akt KiMBI provides a noninvasive and efficient method for in vivo visualization of the PD of Akt inhibitors and degraders.

A molecular grammar governing low-complexity prion-like domain phase separation (PS) has identified tyrosine and arginine as primary drivers via aromatic–aromatic and aromatic–arginine interactions. Here we show that additional residues and contacts contribute to PS, highlighting the need to include these contributions in PS theories and models. Tyrosine and arginine make important contacts beyond tyrosine–tyrosine and tyrosine–arginine, including arginine–arginine contacts. Among polar residues, glutamine contributes to PS with sequence and position specificity, contacting tyrosine, arginine and other residues, both before PS and in condensed phases. The flexibility of glycine enhances PS by allowing favorable contacts between adjacent residues and inhibits the liquid-to-solid transition. Polar residues also make sequence-specific contributions to liquid-to-solid transition, with serine positions linked to the formation of an amyloid-core structure by the FUS low-complexity domain. Hence, an extended molecular grammar expands the role of arginine and polar residues in prion-like domain protein PS and reveals the position dependence of residue contribution to solidification.

Sodium influx and overload are frequently observed in human tissue injuries. Whether sodium overload imposes a causative effect on necrotic cell death and the mechanism involved are unclear. Here we identify necrocide 1 (NC1) as a compound that induces necrotic cell death through sodium overload, termed NECSO for necrosis by sodium overload. NC1 targets the transient receptor potential cation channel subfamily M member 4 (TRPM4), a nonselective monovalent cation channel, to promote Na⁺ influx and necrosis. TRPM4-deficient cells are resistant to NC1-induced NECSO. NC1 specifically activates human TRPM4, not mouse TRPM4, because of differences in a transmembrane region, as revealed by domain swapping and molecular docking. Gain-of-function mutations in human TRPM4 linked to cardiac arrhythmias show increased vulnerability to NECSO triggered by NC1 or 2-deoxy-d-glucose. Chemical screening identified NECSO inhibitors that block necrosis induced by NC1 or energy depletion. These findings provide insights into regulated Na⁺ influx-mediated necrosis and its implications for disease.

Distinct membraneless organelles within cells collaborate closely to organize crucial functions. However, biosynthetic communicating membraneless organelles have yet to be created. Here we report a binary population of membraneless compartments capable of coexistence, biological communication and controllable feedback under cellular environmental conditions. The compartment consortia emerge from two orthogonally phase-separating proteins in a cell-free expression system. Their appearance can be programmed in time and order for on-demand delivery of molecules. In particular, the consortia can sense, process and deliver functional protein cargo in response to a protease message or a DNA message that encodes the protease. Such DNA-based molecular programs can be further harnessed by installing a feedback loop that controls the information flow at the messenger RNA level. These results contribute to understanding crosstalk among membraneless organelles and provide a design principle that can guide construction of functional compartment consortia.

As an enzyme with a critical role in de novo purine synthesis, adenylosuccinate lyase (ADSL) expression is upregulated in various malignancies. However, whether ADSL possesses noncanonical functions that contribute to cancer progression remains poorly understood. Here, we demonstrate that protein kinase R-like endoplasmic reticulum kinase (PERK) activated by lipid deprivation or ER stress phosphorylates ADSL at S140, leading to an enhanced association between ADSL and Beclin1. Beclin1-associated ADSL produces fumarate, which in turn inhibits lysine demethylase 8-mediated Beclin1 demethylation, resulting in enhanced Beclin1 K117me2, subsequent disruption of the binding of BCL-2 to Beclin1 and elevated autophagy. Blocking the ADSL–Beclin1 axis by knock-in mutation or a cell-penetrating peptide inhibits autophagy induced by lipid deprivation and ER stress and blunts liver tumor growth in mice. Additionally, ADSL pS140-upregulated Beclin1 K117me2 levels are positively correlated with autophagy levels in human hepatocellular carcinoma specimens and poor patient prognosis. These findings uncover the function of ADSL in autophagy regulation and liver tumor development.

Diverse bacteria and archaea use atmospheric CO as an energy source for long-term survival. Bacteria use [MoCu]-CO dehydrogenases (Mo-CODH) to convert atmospheric CO to carbon dioxide, transferring the obtained electrons to the aerobic respiratory chain. However, it is unknown how these enzymes oxidize CO at low concentrations and interact with the respiratory chain. Here, we use cryo-electron microscopy and structural modeling to show how Mo-CODH_Ms (CoxSML) from Mycobacterium smegmatis interacts with its partner, the membrane-bound menaquinone-binding protein CoxG. We provide electrochemical, biochemical and genetic evidence that Mo-CODH transfers CO-derived electrons to the aerobic respiratory chain through CoxG. Lastly, we show that Mo-CODH and CoxG genetically and structurally associate in diverse bacteria and archaea. These findings reveal the basis of the biogeochemically and ecologically important process of atmospheric CO oxidation, while demonstrating that long-range quinone transport is a general mechanism of energy conservation, which convergently evolved on multiple occasions.