Structural analysis of the Ras-like G protein MglA and its cognate GAP MglB and implications for bacterial polarity

The small G protein MglA and its cognate GAP MglB exemplify a new type of GTPase activation mechanism. In contrast to other Ras-like proteins, the key 'arginine finger' is provided not by the GAP, but by MglA itself

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Von Proteindomänen zu Wirkstoffkandidaten - Naturstoffe als Leitstrukturen für das Design und die Synthese von Substanzbibliotheken

Die Kombinatorische Chemie hat sich bei der unermüdlichen Suche nach kleinen Molekülen, die die Funktion von Proteinen beeinflussen und letzlich zu neuen Medikamenten führen sollen, als eine sehr wirkungsvolle Methode profiliert. Entgegen der ursprünglichen Erwartung, dass große Substanzbibliotheken zu einer großen Anzahl an Treffern und neuen Leitstrukturen führen, hat sich gezeigt, dass die biologische Relevanz, das Design und die Diversität einer Substanzbibliothek von wesentlich größerer Bedeutung sind. Da die Gesamtheit der denkbaren chemischen Verbindungen unendlich groß ist, stellt sich die Frage nach biologisch validierten Startpunkten für das Bibliotheksdesign. Die Natur selbst gibt eine Antwort: Naturstoffe wurden durch die Evolution darauf selektioniert, an Proteine zu binden. Ergebnisse aus der Strukturbiologie und Bioinformatik belegen, dass die Anzahl an unterschiedlichen Proteinfamilien und Faltungstypen begrenzt ist. Diese strukturelle Selbstbeschränkung der Natur kann für das Design von biologisch relevanten Molekülen genutzt werden, die sich von an die Proteindomänen bindenden Naturstoffen ableiten lassen. Die Fortschritte bei der organischen Festphasensynthese ermöglichen es nun, kombinatorische Substanzbibliotheken auf der Basis komplexer Naturstoffe aufzubauen. Es sollten daher durch die von Naturstoffen inspirierten kombinatorischen Synthesen Leitstrukturen mit höherer Trefferquote und besserer Qualität auffindbar sein

Structural Insights into the Interaction of ROCKI with the Switch Regions of RhoA

The Rho−ROCK pathway modulates the phosphorylation level of a variety of important signaling proteins and is thereby involved in miscellaneous cellular processes including cell migration, neurite outgrowth, and smooth muscle contraction. The observation of the involvement of the Rho−ROCK pathway in tumor invasion and in diseases such as hypertension and bronchial asthma makes it an interesting target for drug development. We herein present the crystal structure of the complex between active RhoA and the Rho−binding domain of ROCKI. The Rho−binding domain structure forms a parallel −helical coiled−coil dimer and, in contrast to the published Rho−protein kinase N structure, binds exclusively to the switch I and II regions of the guanosine 5'−(,−imido)triphosphate−bound RhoA. The switch regions of two different RhoA molecules form a predominantly hydrophobic patch, which is complementarily bound by two identical short helices of 13 residues (amino acids 998−1010). The identified ROCK−binding site of RhoA strikingly supports the assumption of a common consensus−binding site for effector recognition