Iterative model-building, structure refinement, and density modification with the PHENIX AutoBuild Wizard Thomas C. Terwilliger a* , Ralf W. Grosse-Kunstleve b , Pavel V. Afonine b , Nigel W. Moriarty b , Peter Zwart b , Li-Wei Hung a , Randy J. Read c , Paul D. Adams b* a b Los Alamos National Laboratory, Mailstop M888, Los Alamos, NM 87545, USA Lawrence Berkeley National Laboratory, One Cyclotron Road, Bldg 64R0121, Berkeley, CA 94720, USA. c Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK. * Email: terwill@lanl.gov or PDAdams@lbl.gov Running title: The PHENIX AutoBuild Wizard Abstract The PHENIX AutoBuild Wizard is a highly automated tool for iterative model- building, structure refinement and density modification using RESOLVE or TEXTAL model- building, RESOLVE statistical density modification, and phenix.refine structure refinement. Recent advances in the AutoBuild Wizard and phenix.refine include automated detection and application of NCS from models as they are built, extensive model completion algorithms, and automated solvent molecule picking. Model completion algorithms in the AutoBuild Wizard include loop-building, crossovers between chains in different models of a structure, and side-chain optimization. The AutoBuild Wizard has been applied to a set of 48 structures at resolutions ranging from 1.1 A to 3.2 A, resulting in a mean R-factor of 0.24 and a mean free R factor of 0.29. The R-factor of the final model is dependent on the quality of the starting electron density, and relatively independent of resolution. Keywords: Model building; model completion; macromolecular models; Protein Data Bank; structure refinement; PHENIX Introduction Iterative model-building and refinement is a powerful approach to obtaining a complete and accurate macromolecular model. The approach consists of cycles of building an atomic model based on an electron density map for a macromolecular structure, refining the structure, using the refined structure as a basis for improving the map, and building a new model. This type of approach has been carried out in a semi-automated fashion for many years, with manual model-building iterating with automated refinement (Jensen, 1997). More recently, with the development first of ARP/wARP (Perrakis et al., 1999), and later other procedures including RESOLVE iterative model-building and refinement (Terwilliger,

Iterative model-building, structure refinement, and density modification with the PHENIX AutoBuild Wizard

Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.

Microenvironmental regulation of tumour angiogenesis

During the past decade, proof of the principle that peptide receptors can be used successfully for in vivo targeting of human cancers has been provided. The molecular basis for targeting rests on the in vitro observation that peptide receptors can be expressed in large quantities in certain tumors. The clinical impact is at the diagnostic level: in vivo receptor scintigraphy uses radiolabeled peptides for the localization of tumors and their metastases. It is also at the therapeutic level: peptide receptor radiotherapy of tumors emerges as a serious treatment option. Peptides linked to cytotoxic agents are also considered for therapeutic applications. The use of nonradiolabeled, noncytotoxic peptide analogs for long-term antiproliferative treatment of tumors appears promising for only a few tumor types, whereas the symptomatic treatment of neuroendocrine tumors by somatostatin analogs is clearly successful. The present review summarizes and critically evaluates the in vitro data on peptide and peptide receptor expression in human cancers. These data are considered to be the molecular basis for peptide receptor targeting of tumors. The paradigmatic peptide somatostatin and its receptors are extensively reviewed in the light of in vivo targeting of neuroendocrine tumors. The role of the more recently described targeting peptides vasoactive intestinal peptide, gastrin-releasing peptide, and cholecystokinin/gastrin is discussed. Other emerging and promising peptides and their respective receptors, including neurotensin, substance P, and neuropeptide Y, are introduced. This information relates to established and potential clinical applications in oncology.

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Peptide receptors as molecular targets for cancer diagnosis and therapy.

Natural products to drugs: natural product derived compounds in clinical trials

Lipid metabolism, in particular the synthesis of fatty acids (FAs), is an essential cellular process that converts nutrients into metabolic intermediates for membrane biosynthesis, energy storage and the generation of signalling molecules. This Review explores how different aspects of FA synthesis promote tumorigenesis and tumour progression. FA synthesis has received substantial attention as a potential target for cancer therapy, but strategies to target this process have not yet translated into clinical practice. Furthermore, efforts to target this pathway must consider the influence of the tumour microenvironment.

The multifaceted roles of fatty acid synthesis in cancer

Author response: Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

4H-1,2,4-Benzothiadiazine-1,1-dioxide derivatives (I), are new. 4H-1,2,4-Benzothiadiazine-1,1-dioxide derivatives of formula (I), their isomers and salts, are new. X = F, Br, Cl, I, or methyl; and R1, R2 = H or 1-6C alkyl.

Benzothiadiazine-1,1-dioxide derivatives are AMPA receptor modulators, useful in the treatment of memory deficiency, neuro-degenerative disorders, and schizophrenia

New trends in the development of positive allosteric modulators of AMPA receptors

Poupartone B is an alkyl cyclohexenone derivative isolated from Poupartia
 borbonica. This compound demonstrated promising antimalarial activity
 (IC50 < 1 µg/mL), however, it was not
 devoid of toxicity. Thus, to reduce the adverse side effects of this natural
 bioactive molecule, a delivery strategy involving a nanostructure was
 formulated. Additionally, poupartone B-loaded liposomes were coated with
 heparin, a glycosaminoglycan that is known to target proteins on the surface of
 Plasmodium falciparum-infected red blood cells. The quantification of
 the compound in the formulation was performed by HPLC-DAD, while heparin was
 quantitated by 1H NMR spectroscopy. The liposomes’
 antiplasmodial activity was tested on artemisinin-resistant P. falciparum
 isolate, and toxicity was evaluated on human HeLa cells and zebrafish embryos.
 Throughout this research, the formulation demonstrated higher antiplasmodial
 activities against both P. falciparum strains and a significant decrease
 of in vitro toxicity. The formulation improved the selectivity index 2
 times in vitro and proved to be 3 times less toxic than the compound
 alone in the zebrafish embryo acute toxicity test. Hence, the use of this
 strategy to deliver natural products in Plasmodium-infected cells,
 particularly those with a narrow therapeutic margin, is proposed.

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Heparin-Coated Liposomes Improve Antiplasmodial Activity and Reduce the Toxicity of Poupartone B

Gut microbiota (GM) has been involved in the pathophysiology of hypertension (HT), notably via short chain fatty acids (SCFAs). Among the clinical manifestations of HT, the absence of a significant...

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Pascal De Tullio

Papers

Author response: Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

Benzothiadiazine-1,1-dioxide derivatives are AMPA receptor modulators, useful in the treatment of memory deficiency, neuro-degenerative disorders, and schizophrenia

New trends in the development of positive allosteric modulators of AMPA receptors

Heparin-Coated Liposomes Improve Antiplasmodial Activity and Reduce the Toxicity of Poupartone B

The faecal abundance of short chain fatty acids is increased in men with a non-dipping blood pressure profile.