Menin is an essential oncogenic co-factor of MLL1 fusion proteins in acute leukemias and inhibitors of the menin-MLL1 interaction are under evaluation in clinical trials. Recent studies found emerging resistance to menin inhibitor treatment in leukemia patients as a result of somatic mutations in menin. To understand how patient mutations in menin affect the interaction with MLL1, we performed systematic characterization of the binding affinity of these menin mutants (T349M, M327I, G331R and G331D) and the N-terminal fragment of MLL1.

Dynamic ADP-ribosylation signaling is a crucial pathway that controls fundamental cellular processes, in particular, the response to cellular stresses such as DNA damage, reactive oxygen species, and infection. In some pathogenic microbes, the response to oxidative stress is controlled by a SirTM/zinc-containing macrodomain (Zn-Macro) pair responsible for establishment and removal of the modification, respectively. Targeting this defence mechanism against the host’s innate immune response may lead to novel approaches to support the fight against emerging antimicrobial resistance.

The non-heme iron-dependent dioxygenase 2-aminoethanethiol (aka cysteamine) dioxygenase (ADO) has recently been identified as an enzymatic oxygen sensor that coordinates cellular changes to hypoxia by regulating the stability of proteins bearing an N-terminal cysteine (Nt-cys) through the N-degron pathway. It catalyzes O2-dependent Nt-cys sulfinylation, which promotes proteasomal degradation of the target. Only a few ADO substrates have been verified, including regulators of G-protein signaling (RGS) 4 and 5, and the proinflammatory cytokine interleukin-32, all of which exhibit cell and/or tissue specific expression patterns.

HLA-DQ molecules drive unwanted alloimmune responses after solid-organ transplants and several autoimmune diseases, including type 1 diabetes and celiac disease. Biologics with HLA molecules as part of the design are emerging therapeutic options for these allo- and autoimmune conditions. However, the soluble α and β chains of class II HLA molecules do not dimerize efficiently without their transmembrane domains, which hinders their production. In this study, we examined the feasibility of interchain disulfide engineering by introducing paired cysteines to juxtaposed positions in the α and β chains of HLA-DQ7, encoded by HLA-DQA1∗05:01 and HLA-DQB1∗03:01 respectively.

Reverse transcriptases (RTs) are enzymes with DNA polymerase and RNase H activities. They convert ssRNA into dsDNA and are key enzymes for the replication of retroviruses and retroelements. Caulimoviridae is a major family of plant-infecting viruses. Caulimoviruses have a circular dsDNA genome that is replicated by reverse transcription, but in contrast to retroviruses, they lack integrase. Caulimoviruses are related to Ty3 retroelements. Ty3 RT has been extensively studied structurally and biochemically, but corresponding information for caulimoviral RTs is unavailable.