抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

J. Appl. Cryst.の発刊に際して

Here, we describe two freely available web servers for molecular docking. The PatchDock method performs structure prediction of protein-protein and protein-small molecule complexes. The SymmDock method predicts the structure of a homomultimer with cyclic symmetry given the structure of the monomeric unit. The inputs to the servers are either protein PDB codes or uploaded protein structures. The services are available at http://bioinfo3d.cs.tau.ac.il. The methods behind the servers are very efficient, allowing large-scale docking experiments.

PatchDock and SymmDock: servers for rigid and symmetric docking

The phosphoinositide 3-kinase (PI3K) pathway is a key signal transduction system that links oncogenes and multiple receptor classes to many essential cellular functions, and is perhaps the most commonly activated signalling pathway in human cancer. This pathway therefore presents both an opportunity and a challenge for cancer therapy. Even as inhibitors that target PI3K isoforms and other major nodes in the pathway, including AKT and mammalian target of rapamycin (mTOR), reach clinical trials, major issues remain. Here, we highlight recent progress that has been made in our understanding of the PI3K pathway and discuss the potential of and challenges for the development of therapeutic agents that target this pathway in cancer.

/pdf/targeting-the-phosphoinositide-3-kinase-pathway-in-cancer-4zhc81tbx0.pdf

Targeting the phosphoinositide 3-kinase pathway in cancer.

There are ample genetic and laboratory studies that suggest the PI3K-Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K-Akt signalling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clinical development.

/pdf/targeting-pi3k-signalling-in-cancer-opportunities-challenges-22a9u88icu.pdf

Targeting PI3K signalling in cancer: opportunities, challenges and limitations.

Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3Kalpha, with oncogenic mutations identified in both the p110alpha catalytic and the p85alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110alpha in a complex with the p85alpha inter-Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.

https://science.sciencemag.org/content/sci/317/5835/239.full.pdf

Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit.

We present a very efficient rigid "unbound" soft docking methodology, which is based on detection of geometric shape complementarity, allowing liberal steric clash at the interface. The method is based on local shape feature matching, avoiding the exhaustive search of the 6D transformation space. Our experiments at CAPRI rounds 1 and 2 show that although the method does not perform an exhaustive search of the 6D transformation space, the "correct" solution is never lost. However, such a solution might rank low for large proteins, because there are alternatives with significantly larger geometrically compatible interfaces. In many cases this problem can be resolved by successful a priori focusing on the vicinity of potential binding sites as well as the extension of the technique to flexible (hinge-bent) docking. This is demonstrated in the experiments performed as a lesson from our CAPRI experience.

/pdf/taking-geometry-to-its-edge-fast-unbound-rigid-and-hinge-3pg37frzok.pdf

Taking geometry to its edge: fast unbound rigid (and hinge-bent) docking.

Predicting molecular interactions is a major goal in rational drug design. Pharmacophore, which is the spatial arrangement of features that is essential for a molecule to interact with a specific target receptor, is an important model for achieving this goal. We present a freely available web server, named PharmaGist, for pharmacophore detection. The employed method is ligand based. Namely, it does not require the structure of the target receptor. Instead, the input is a set of structures of drug-like molecules that are known to bind to the receptor. The output consists of candidate pharmacophores that are computed by multiple flexible alignment of the input ligands. The method handles the flexibility of the input ligands explicitly and in deterministic manner within the alignment process. PharmaGist is also highly efficient, where a typical run with up to 32 drug-like molecules takes seconds to a few minutes on a stardard PC. Another important characteristic is the capability of detecting pharmacophores shared by different subsets of input molecules. This capability is a key advantage when the ligands belong to different binding modes or when the input contains outliers. The webserver has a user-friendly interface available at http://bioinfo3d.cs.tau.ac.il/PharmaGist.

/pdf/pharmagist-a-webserver-for-ligand-based-pharmacophore-44tx16w15s.pdf

PharmaGist: a webserver for ligand-based pharmacophore detection

We present a set of geometric docking algorithms for rigid, flexible, and cyclic symmetry docking. The algorithms are highly efficient and have demonstrated very good performance in CAPRI Rounds 3-5. The flexible docking algorithm, FlexDock, is unique in its ability to handle any number of hinges in the flexible molecule, without degradation in run-time performance, as compared to rigid docking. The algorithm for reconstruction of cyclically symmetric complexes successfully assembles multimolecular complexes satisfying C(n) symmetry for any n in a matter of minutes on a desktop PC. Most of the algorithms presented here are available at the Tel Aviv University Structural Bioinformatics Web server (http://bioinfo3d.cs.tau.ac.il/).

Yuval Inbar

Papers

PatchDock and SymmDock: servers for rigid and symmetric docking

Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit.

Taking geometry to its edge: fast unbound rigid (and hinge-bent) docking.

PharmaGist: a webserver for ligand-based pharmacophore detection

Geometry-based flexible and symmetric protein docking.