Structural biology

About: Structural biology is a research topic. Over the lifetime, 2206 publications have been published within this topic receiving 126070 citations.

CD Spectroscopy and the Helix-Coil Transition in Peptides and Polypeptides

Abstract: The proposal by Pauling and his coworkers (1951) of an atomic model for the structure of the alpha helix stimulated research in several areas of protein chemistry It excited chemists as few discoveries have before or since, giving impetus to structural modeling efforts that resulted in the structure of DNA 2 years later, and in a whole new field of structural biology within two decades Pauling’s feat pointed out the importance of understanding the conformation of the peptide group itself, rather than building models based on idealized helical structures Working on the same problem, Bragg et al (1950) failed to produce a structure of comparable elegance because they were unaware the peptide bond was planar (Crick, 1988) The alpha helix could be identified in the diffraction patterns from crystals of the globular proteins myoglobin and hemoglobin, as well as in the classical “α” patterns from fibrous proteins like keratin and synthetic polypeptides, poly(γ-l-glutamate) being the first to show the α pattern (Elliott, 1967)

Insights into the Role of Asp792.50 in β2 Adrenergic Receptor Activation from Molecular Dynamics Simulations

Abstract: Achieving a molecular-level understanding of G-protein-coupled receptor (GPCR) activation has been a long-standing goal in biology and could be important for the development of novel drugs. Recent breakthroughs in structural biology have led to the determination of high-resolution crystal structures for the β2 adrenergic receptor (β2AR) in inactive and active states, which provided an unprecedented opportunity to understand receptor signaling at the atomic level. We used molecular dynamics (MD) simulations to explore the potential roles of ionizable residues in β2AR activation. One such residue is the strongly conserved Asp792.50, which is buried in a transmembrane cavity and becomes dehydrated upon β2AR activation. MD free energy calculations based on β2AR crystal structures suggested an increase in the population of the protonated state of Asp792.50 upon activation, which may contribute to the experimentally observed pH-dependent activation of this receptor. Analysis of MD simulations (in total >100 μs)...

Structure-based functional inference in structural genomics.

Abstract: The dramatically increasing number of new protein sequences arising from genomics 4 proteomics requires the need for methods to rapidly and reliably infer the molecular and cellular functions of these proteins. One such approach, structural genomics, aims to delineate the total repertoire of protein folds in nature, thereby providing three-dimensional folding patterns for all proteins and to infer molecular functions of the proteins based on the combined information of structures and sequences. The goal of obtaining protein structures on a genomic scale has motivated the development of high throughput technologies and protocols for macromolecular structure determination that have begun to produce structures at a greater rate than previously possible. These new structures have revealed many unexpected functional inferences and evolutionary relationships that were hidden at the sequence level. Here, we present samples of structures determined at Berkeley Structural Genomics Center and collaborators’ laboratories to illustrate how structural information provides and complements sequence information to deduce the functional inferences of proteins with unknown molecular functions. Two of the major premises of structural genomics are to discover a complete repertoire of protein folds in nature and to find molecular functions of the proteins whose functions are not predicted from sequence comparison alone. To achieve these objectives on a genomic scale, new methods, protocols, and technologies need to be developed by multi-institutional collaborations worldwide. As part of this effort, the Protein Structure Initiative has been launched in the United States (PSI; www.nigms.nih.gov/funding/psi.html). Although infrastructure building and technology development are still the main focus of structural genomics programs [1−6], a considerable number of protein structures have already been produced, some of them coming directly out of semi-automated structure determination pipelines [6−10]. The Berkeley Structural Genomics Center (BSGC) has focused on the proteins of Mycoplasma or their homologues from other organisms as its structural genomics targets because of the minimal genome size of the Mycoplasmas as well as their relevance to human and animal pathogenicity (http://www.strgen.org). Here we present several protein examples encompassing a spectrum of functional inferences obtainable from their three-dimensional structures in five situations, where the inferences are new and testable, and are not predictable from protein sequence information alone.

Structural hot spots for the solubility of globular proteins

Abstract: Natural selection shapes protein solubility to physiological requirements and recombinant applications that require higher protein concentrations are often problematic. This raises the question whether the solubility of natural protein sequences can be improved. We here show an anti-correlation between the number of aggregation prone regions (APRs) in a protein sequence and its solubility, suggesting that mutational suppression of APRs provides a simple strategy to increase protein solubility. We show that mutations at specific positions within a protein structure can act as APR suppressors without affecting protein stability. These hot spots for protein solubility are both structure and sequence dependent but can be computationally predicted. We demonstrate this by reducing the aggregation of human α-galactosidase and protective antigen of Bacillus anthracis through mutation. Our results indicate that many proteins possess hot spots allowing to adapt protein solubility independently of structure and function. Mutations in aggregation prone regions of recombinant proteins often improve their solubility, although they might cause negative effects on their structure and function. Here, the authors identify proteins hot spots that can be exploited to optimize solubility without compromising stability.