Curved beta sheets are important for the architecture of protein cavities, such as enzyme active sites and ligand-binding pockets. Beginning by analyzing classic protein formations and running folding simulations, University of Washington (UW) researchers under the leadership of David Baker designed six protein folds inspired by naturally occurring protein superfamilies. A research report published in the January 13 issue of Science describes how a multi-institutional team of scientists compared the predicted models to physical structures of these designed proteins.
Three Is Not a Crowd: Designed Metalloprotein Trimer Provides Stable Platform for Further Development
University of Washington (UW) researchers have designed a novel protein with properties that could lead to the generation of new photoactive proteins. This three-fold symmetric, self-assembling protein homotrimer contains a highly stable noncanonical amino acid. Noncanonical amino acids are not found among the 20 encoded amino acids in the body and can contain modifications to allow for new functionality. In this case, this amino acid contains a bipyridine group that chelates metal, thereby introducing new photochemical properties into the protein interface, and nucleating the formation of the homotrimer.
An article published last month in PNAS describes this work from a team of scientists led by David Baker at UW, which included Jose Henrique Pereira, Banumathi Sankaran, and Peter Zwart of the Molecular Biophysics & Integrated Bioimaging Division (MBIB). The MBIB scientists developed the crystal screen that was used to crystallize the novel protein and performed X-ray crystallography on Beamline 8.2.1 in the Berkeley Center for Structural Biology at the Advanced Light Source. Their X-ray crystallographic analysis of the homotrimer showed that the design process had near-atomic-level accuracy, demonstrating that computational protein design together with the utilization of noncanonical amino acids could be used to generate novel protein functions. These methods could be used to develop new therapeutics, biomaterials, and metalloproteins with useful optical or photochemical properties.
Two Basic Mechanisms of Cardiovascular Drugs
Calcium channel blockers are widely prescribed for heart and blood-vessel diseases. With the help of the high-intensity x-ray beams and remotely controlled robots at the Advanced Light Source (ALS), two groups of scientists from University of Washington have revealed, at atomic resolution, how two different classes of calcium channel blocker drugs produce their therapeutic effects. The researchers took advantage of the remotely controllable robot automounter available in the Berkeley Center for Structural Biology at the ALS to screen a large number of crystals for the best diffraction. The tunable x-ray source also allowed them to collect anomalous diffraction data at Beamlines 8.2.1 and 8.2.2 with bromine-incorporated drugs, which was critical for locating the drug molecules in the crystal. The results pave the way for optimizing these classic compounds for safer and more reliable pharmaceutical applications. Read the ALS Science Highlight.
Finding Diamonds in the Rough
New crystallography finding by JBEI and GLBRC benefits bioenergy industry
During the kraft process used to convert wood into wood pulp, the structural material lignin is partially converted into molecules like stilbene. Stilbenes are also naturally occurring in plants and some bacteria, and may play a role in plant pathogen resistance.
Currently, the deconstruction of plant biomass into cellulose and lignin is an expensive process. Lignin accounts for about 30 percent of plant cell wall carbon, and its conversion into chemicals or fuels could have a significant positive impact on the economics of processing lignocellulosic biomass. Enzymes capable of producing useful compounds from the breakdown of stilbenes and similar molecules could be employed for this. Collaborators from two of the Department of Energy Bioenergy Research Centers now have gained first-hand insight into how a stilbene cleaving oxygenase (SCO) carries out this unusual chemical reaction.
Understanding the Key to Henipavirus Infection
In 1994, a virus emerged in Hendra, Australia, causing respiratory and neurological diseases. It was transmissible from horses to humans, with a mortality rate of 57% in humans and 89% in horses. Since then 2 additional deadly species have emerged in Malaysia and Africa, with evidence of 19 more. The members of this Paramyxoviridae family infect host cells through the fusion protein, F, which is embedded in the viral particle membrane. The bulk of the F protein, the ectodomain, protrudes from the membrane’s surface and undergoes a dramatic refolding to merge the virus and host membranes. At the Advanced Light Source (ALS) Beamline 8.2.2 in the Berkeley Center for Structural Biology, researchers used macromolecular crystallography to study the structure of the Hendra F protein ectodomain in its prefusion form and gain insight into its function. Read the ALS Science Brief.
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