Recent clinical trials using immunotherapy demonstrate its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies such as anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-Programmed cell death protein 1/anti-Programmed death-ligand 1 (anti-PD-1/anti-PD-L1)1 have demonstrated durable clinical responses in various cancers. Although these new immunotherapies have significant impact on cancer treatment, multiple mechanisms of immune resistance exist in tumors. Among the key mechanisms, myeloid cells play a major role in limiting effective tumor immunity. 2–4 Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. 5,6 These observations suggest a need for a precision medicine approach where the design of the immunotherapeutic combinations are tailored based on tumor immune landscape to overcome such resistance mechanisms. Herein we employ a preclinical model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumors. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3K-γ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3K–γ, with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumor immune microenvironment and promote cytotoxic T cell-mediated tumor regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3K-γ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumors.

Methicillin-resistant Staphylococcus aureus infection can be treated effectively by combining a β-lactam antibiotic with a drug that targets FtsZ.

Several genes from prokaryotes and lower eukaryotes have been found to contain an in-frame open reading frame, which encodes for an internal protein (intein). Post-translationally, the internal polypeptide auto-splices and ligates the external sequences to yield a functional external protein (extein) and an intein. Most, but not all inteins, contain, apart from a splicing domain, a separate endonucleolytic domain that enables them to maintain their presence by a homing mechanism. We report here the crystal structure of an intein found in the gyrase A subunit from Mycobacterium xenopi at 2.2 A resolution. The structure contains an unusual beta-fold with the catalytic splice junctions at the ends of two adjacent antiparallel beta-strands. The arrangement of the active site residues Ser 1, Thr 72, His 75, His 197, and Asn 198 is consistent with a four-step mechanism for the cleavage-ligation reaction. Using site-directed mutagenesis, the N-terminal cysteine, proposed as the nucleophile in the first step of the splicing reaction, was changed to a Ser 1 and Ala 0, thus capturing the intein in a pre-spliced state.

Snake venoms are cocktails of enzymes and non‐enzymatic proteins used for both the immobilization and digestion of prey. The most common snake venom enzymes include acetylcholinesterases, l‐amino acid oxidases, serine proteinases, metalloproteinases and phospholipases A2. Higher catalytic efficiency, thermal stability and resistance to proteolysis make these enzymes attractive models for biochemists, enzymologists and structural biologists. Here, we review the structures of these enzymes and describe their structure‐based mechanisms of catalysis and inhibition. Some of the enzymes exist as protein complexes in the venom. Thus we also discuss the functional role of non‐enzymatic subunits and the pharmacological effects of such protein complexes. The structures of inhibitor–enzyme complexes provide ideal platforms for the design of potent inhibitors which are useful in the development of prototypes and lead compounds with potential therapeutic applications.

Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.