Visualization and analysis of non-covalent contacts using the Protein Contacts Atlas

Visualizations of biomolecular structures empower us to gain insights into biological functions, generate testable hypotheses, and communicate biological concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiology, pathogenesis, and drug action, are seldom visualized. We present the Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and analysis of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes. The Protein Contacts Atlas enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces, and protein–ligand contacts and by mapping external information. The Protein Contacts Atlas is available at and also through PDBe.

The paper by Kayikci and Venkatakrishnan et al can be found here

Pharmacogenomics of GPCR Drug Targets

Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants could increase prescription precision, improving patients’ quality of life, and relieve the economic and societal burden due to variable drug responsiveness.

The paper by Hauser et al can be found here and the video abstract can be found here

Melis Kayikci is our group’s Scientific Manager

Many congratulations to Dr. Melis Kayikci, who has been officially promoted to become our group’s Scientific Manager from the 1st of April 2014! Melis will now oversee various scientific administrative responsibilities in our group in addition to providing scientific support with computing and research.

Melis Kayikci

Our perspective on the hidden codes that constrain protein evolution is published in Science

In this essay, we discuss how regulatory elements within protein-coding regions (such as transcription factor binding) can influence codon choice and amino acid preference that are independent of protein structure or function. We discuss how there may be conflicts between codes and highlight that the redundancy in the genetic code might facilitate the existence of multiple overlapping regulatory codes within protein-coding regions of the genome. You can read the Perspective here.

Molecular signatures of G-protein-coupled receptors published in Nature

In this work, we objectively compare known structures and reveal key similarities and differences among diverse GPCRs. We identify a consensus structural scaffold of GPCRs that is constituted by a network of non-covalent contacts between residues on the transmembrane helices. By systematically analysing structures of the different receptor–ligand complexes, we identify a consensus ‘ligand-binding cradle’ that constitutes the bottom of the ligand-binding pocket within the TM bundle. Furthermore, our comparative study suggests that the third TM helix has a central role as a structural and functional hub. The paper can be found here and the press release by MRC can be found here. Our work was No. 1 in Nature’s top 10 downloaded articles in February 2013, featured in Nature’s GPCR focus section and mentioned in the cover page.

Network based approach to study DNA-DNA contacts published in Nucleic Acids Research

In this paper, we present a general statistical framework that is widely applicable to the analysis of genomic contact maps, irrespective of the data acquisition and normalization processes. Within this framework DNA–DNA contact data are represented as a complex network where DNA segments and contacts between them are denoted as nodes and edges, respectively. We also present a robust method for generating randomized contact networks that explicitly take into account the inherent 3D nature of the genome and serve as realistic null-models for unbiased statistical analyses. Our paper was chosen as a featured article by NAR. The paper by Kai Kruse et al can be found here.

Strategies to control functional and non-functional aggregation published in Cell Reports

Growing evidence suggests that aggregation-prone proteins are both harmful and functional for a cell. How do cellular systems balance the detrimental and beneficial effect of protein aggregation? In this work, we reveal that aggregation-prone proteins are subject to differential transcriptional, translational, and degradation control compared to nonaggregation-prone proteins, which leads to their decreased synthesis, low abundance, and high turnover. Genetic modulators that enhance the aggregation phenotype are enriched in genes that influence expression homeostasis. Moreover, genes encoding aggregation-prone proteins are more likely to be harmful when overexpressed. The trends are evolutionarily conserved and suggest a strategy whereby cellular mechanisms specifically modulate the availability of aggregation-prone proteins to (1) keep concentrations below the critical ones required for aggregation and (2) shift the equilibrium between the monomeric and oligomeric/aggregate form, as explained by Le Chatelier’s principle. This strategy may prevent formation of undesirable aggregates and keep functional assemblies/aggregates under control. The paper can be found here.

Welcome to Balaji Santhanam!

Dr. Balaji Santhanam from Harvard University has just started as a new Senior Investigator Scientist at the LMB. A very warm welcome from all of us Balaji. We are looking forward to some very exciting discussions and science in the coming days.