Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides

Sactipeptides are ribosomally synthesized peptides that contain a characteristic thioether bridge (sactionine bond) that is installed posttranslationally and is absolutely required for their antibiotic activity. Sactipeptide biosynthesis requires a unique family of radical SAM enzymes, which contain multiple [4Fe-4S] clusters, to form the requisite thioether bridge between a cysteine and the α-carbon of an opposing amino acid through radical-based chemistry. Here we present the structure of the sactionine bond-forming enzyme CteB, from Clostridium thermocellum ATCC 27405, with both SAM and an N-terminal fragment of its peptidyl-substrate at 2.04 Å resolution. CteB has the (β/α)6-TIM barrel fold that is characteristic of radical SAM enzymes, as well as a C-terminal SPASM domain that contains two auxiliary [4Fe-4S] clusters. Importantly, one [4Fe-4S] cluster in the SPASM domain exhibits an open coordination site in absence of peptide substrate, which is coordinated by a peptidyl-cysteine residue in the bound state. The crystal structure of CteB also reveals an accessory N-terminal domain that has high structural similarity to a recently discovered motif present in several enzymes that act on ribosomally synthesized and post-translationally modified peptides (RiPPs), known as a RiPP precursor peptide recognition element (RRE). This crystal structure is the first of a sactionine bond forming enzyme and sheds light on structures and mechanisms of other members of this class such as AlbA or ThnB

Anti-CTLA-4 therapy requires an Fc domain for efficacy

Item does not contain fulltextIpilimumab, a monoclonal antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved "checkpoint"-blocking anticancer therapy. In mouse tumor models, the response to antibodies against CTLA-4 depends entirely on expression of the Fcgamma receptor (FcgammaR), which may facilitate antibody-dependent cellular phagocytosis, but the contribution of simple CTLA-4 blockade remains unknown. To understand the role of CTLA-4 blockade in the complete absence of Fc-dependent functions, we developed H11, a high-affinity alpaca heavy chain-only antibody fragment (VHH) against CTLA-4. The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically. We used H11 to visualize CTLA-4 expression in vivo using whole-animal immuno-PET, finding that surface-accessible CTLA-4 is largely confined to the tumor microenvironment. Despite this, H11-mediated CTLA-4 blockade has minimal effects on antitumor responses. Installation of the murine IgG2a constant region on H11 dramatically enhances its antitumor response. Coadministration of the monovalent H11 VHH blocks the efficacy of a full-sized therapeutic antibody. We were thus able to demonstrate that CTLA-4-binding antibodies require an Fc domain for antitumor effect

Price and Nonprice Competition with Endogenous Market Structure

This paper examines the effect of the intensity of short-run price competition and other exogenous variables that affect gross profit margins - such as the degree of product differentiation and the consumers' responsiveness to quality - on market structure and on advertising and R & D expenditure. A key result is that more intense short-run competition can lead to lower concentration in industries with high advertising or R & D intensity, unlike exogenous-sunk-cost industries. Also, price competition has a negative effect on advertising or R & D expenditure. A case study is also presented, which is consistent with the theoretical results of the paper

Investigation of major international and Turkish companies via hierarchical methods and bootstrap approach

We present a study, within the scope of econophysics, of the hierarchical structure of 98 among the largest international companies including 18 among the largest Turkish companies, namely Banks, Automobile, Software-hardware, Telecommunication Services, Energy and the Oil-Gas sectors, viewed as a network of interacting companies. We analyze the daily time series data of the Boerse-Frankfurt and Istanbul Stock Exchange. We examine the topological properties among the companies over the period 2006-2010 by using the concept of hierarchical structure methods (the minimal spanning tree (MST) and the hierarchical tree (HT)). The period is divided into three subperiods, namely 2006-2007, 2008 which was the year of global economic crisis, and 2009-2010, in order to test various time-windows and observe temporal evolution. We carry out bootstrap analyses to associate the value of statistical reliability to the links of the MSTs and HTs. We also use average linkage clustering analysis (ALCA) in order to better observe the cluster structure. From these studies, we find that the interactions among the Banks/Energy sectors and the other sectors were reduced after the global economic crisis; hence the effects of the Banks and Energy sectors on the correlations of all companies were decreased. Telecommunication Services were also greatly affected by the crisis. We also observed that the Automobile and Banks sectors, including Turkish companies as well as some companies from the USA, Japan and Germany were strongly correlated with each other in all periods

A dynamic analysis of interactive rationality

Abstract. Epistemic game theory has shown the importance of informational contexts in understanding strategic interaction. We propose a general framework to analyze how such contexts may arise. The idea is to view informational contexts as the fixed-points of iterated, “rational responses ” to incoming information about the agents ’ possible choices. We show general conditions for the stabilization of such sequences of rational responses, in terms of structural properties of both the decision rule and the information update policy.