Stanford Synchrotron Radiation Lightsource

Every year the flu vaccine contains a different formulation, due to multiple influenza virus strains and their ability to mutate. Scientists are working toward the universal flu vaccine, which would target conserved regions of the virus. Such a vaccine would be effective regardless of virus strain or genetic drift due to mutation, requiring no yearly updates. Current research focuses on the virus’s hemagglutinin (HA) stem region, which is targeted by our immune system’s broadly neutralizing antibodies (bnAbs). A team of researchers from Scripps and Janssen developed bnAbs to HA, which proved successful in preventing influenza infection in mice. Some of these are now being evaluated for effectiveness in human clinical trials. The team is now focused on finding an effective small molecule based on their bnAbs, which would have the advantage of oral delivery.

Iron-sulfur (Fe-S) clusters are cofactors that are required for the function of proteins in many critical cellular processes.  All living organisms synthesize and distribute Fe-S clusters using complex biosynthetic pathways. In humans, the mitochondrial cysteine desulfurase, NFS1, is responsible for the conversion of the sulfur-containing amino acid, cysteine, to alanine and persulfide sulfur, an intermediate in Fe-S cluster synthesis. In contrast to the analogous cysteine desulfurase in prokaryotes, the eukaryotic NFS1 enzyme requires accessory proteins, ISD11 and ACP, for its function. A team of scientists investigated the structure of the NFS1-ISD11-ACP complex in order to unravel NFS1’s requirement of ISD11 and ACP for function.

The presence of the receptor tyrosine kinase Axl on tumor cells is correlated with disease severity and thus is an important oncology target. Developing inhibitors to Axl has been met with limited success due to the tight affinity with which Axl binds its ligand, growth arrest-specific 6 (Gas6). Researchers have engineered a soluble “receptor decoy,” called MYD1, based on Axl’s ligand-binding domain, that binds Gas6 even more tightly than Axl does.  

Many bacteria, including many colonizing our own gut biomes, produce hair-like pili structures on their surfaces. There are various types of pili used for different purposes, like exchanging genetic information (conjugation), movement, and adhesion. A bacterium builds pilus through oligomerization of protein subunits. A group of scientists have determined the structure of a new type of pilus, which they named the type V pilus.

Mutation of the gene coding for the BRAF kinase, an important enzyme in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, can lead to melanoma, an aggressive skin cancer. The pharmaceutical company Plexxikon has developed drugs, like vemurafenib, that treat metastatic melanoma harboring BRAF mutation.

Scientists have determined the 3-D structure of a complex of synaptic proteins that controls the release of signaling chemicals from brain cells in less than one-thousandth of a second, which ultimately could help unlock a new realm of drug research targeting brain disorders.

As a basic biological building block of amino acids and DNA, nitrogen is necessary for life. Yet most of the Earth’s nitrogen is contained in the atmosphere as dinitrogen, which most organisms are unable to use because they cannot break dinitrogen’s N-N-triple bond. A few microorganisms, however, are able to use an enzyme called nitrogenase to catalyze the transformation of dinitrogen into bioavailable ammonia.

Fatty acids are key components of a variety of biological functions ranging from cellular membranes to energy storage. In addition, they are of great interest as potential “green” biofuels and targets in the development of novel antibiotics. In order to fully exploit their potential, researchers must first understand in detail how organisms synthesize fatty acids. However, due to the dynamic nature of the process, structural and functional studies of fatty acid biosynthesis are very challenging. A team of scientists has recently made a giant leap forward by determining the structure of a protein–protein complex that represents a snapshot of fatty acid biosynthesis in action.

UCE plays a key role in the functioning of lysosomes, cellular sacs full of digestive enzymes that break down bacteria, viruses and worn-out cell parts for recycling. When this recycling process goes awry, it can cause rare metabolic diseases such as Tay-Sachs and Gaucher, which often cause death in affected children by their early teens. Three years ago, researchers discovered that three mutations in UCE itself were linked to persistent stuttering that is passed down in families.

Cys-loop receptors in eukaryotic cells control fast synaptic transmission and are important targets for various therapeutics which include general anesthetics. Although technical challenges have limited the determination of high-resolution structures for Cys-loop receptors, researchers from the University of Pittsburgh School of Medicine have taken advantage of two homologous proteins: the pentameric ligand-gated ion channels (pLGICs) found in the bacterium Erwinia chrysanthemi (ELIC) and the cyanobacterium Gloebacter violaceus (GLIC). The researchers carried out crystallographic studies of these pLGICs on SSRL Beam Line 12-2, investigating the structural underpinnings of the pLGIC activation process and the structural basis of anesthetic modulation of pLGICs.

Wnt proteins engage an array of receptors and inhibitors to precisely regulate crucial processes during embryonic development and tissue homeostasis and repair in the adult, and deregulated Wnt signaling is observed in many types of cancers and degenerative diseases.

Understanding the physical underpinnings of how proteins interact specifically with one another and not with the myriad other molecules that coexist in every cellular compartment is a major goal of molecular biology. The broad outlines of an answer were suggested by Linus Pauling in the 1940’s: the aggregate effect of numerous weak and nonspecific van der Waals, hydrogen-bonding, and electrostatic interactions underlie high specificity and affinity. Since Pauling’s days thousands of co-crystal structures have provided concrete examples for how molecular recognition is achieved in different biological contexts. Yet, the ultimate proof for understanding a natural phenomenon lies in recapitulating it; in the words of Thomas Edison, ‘until man duplicates a single blade of grass, Nature laughs at his so-called scientific knowledge’.

Autism is considered among the most devastating neurological disorder conditions of early childhood. Now, researchers working in part at SSRL's Beam Line 4-2 have determined a three-dimensional structural model of a complex with the only two extracellular synaptic proteins implicated in autism spectrum disorders and mental retardation. Such a finding could deepen our understanding of this mysterious and debilitating type of disorder. The findings were published in the June 2007 edition of the journal Structure.

Autism is a neurodevelopmental disorder that impairs social interactions, and causes communication deficits and repetitive behaviors. About 1 in every 150 children is affected by autism. Genetic screens revealed that mutations in the neurexin and neuroligin genes are among the multiple genetic causes of autism spectrum disorders and mental retardation (Jamain et al., 2003; Szatmari et al., 2007).

Stanford University School of Medicine scientists working in part at SSRL's Beam Line 11-1 have uncovered new molecular insights to the mechanism behind immune disorders such as asthma. Using protein x-ray crystallography at 3.0 Angstrom resolution, researchers Sherry LaPorte and Chris Garcia solved three structures of two signaling proteins known as "cytokines" in complex with their shared receptors, where these molecules help regulate immune system activity. The study was published as the cover story in the January 25 edition of the journal Cell.

Using macromolecular crystallography techniques, the team solved the structure of a protein on the Ebolavirus's surface, called glycoprotein GP, in complex with a rare antibody identified in a human survivor. The glycoprotein-antibody complex proved especially challenging to crystallize and subsequently, to yield well-diffracting crystals. The team grew ~50,000 crystal samples and screened 800 of the largest, using in part the highly-automated robotics hardware and software at the SSRL beam lines, before finding a sample that would diffract to 3.4 Angstroms.

Scientists have recently identified a family of human antibodies that can take out an unprecedented number of different types of flu viruses, including H5N1 'bird flu' and the 1918 H1N1 'Spanish flu', which killed millions around the world during World War I, as well as seasonal flu. Using SSRL's Beam Line 9-2, Dr. Robert Liddington from the Burnham Institute for Medical Research led a team of scientists that determined the crystal structure of one such antibody, F10, in complex with the hemagglutinin H5 to unveil the molecular mechanism of virus neutralization. Results were published online 22 February 2009 in the journal Nature Structural and Molecular Biology.

In order for our eyes to see in both intense and low light conditions, molecular mechanisms allow for light and dark adaptation. The G-protein transducin is responsible for transducing signal from the photon receptor protein rhodopsin in rod and cone photoreceptors of our retina. Transducin is composed of three polypeptides, α, β and γ. The α subunit contains the GTP binding site. While waiting for a signal from rhodopsin, transducin is bound to the outer segment of the neuron. During exposure to normal daylight, transducin becomes displaced and migrates to another part of the cell: the photoreceptor is adapting to light. In darkness or very dim light, transducin will return to its “home” membrane. 

The capsid that surrounds viruses is formed from subunit proteins that interact in specific ways to form a tight shell. The processes of coming together and forming interactions are multistep and complex and are fundamental events to acquire viral infectivity. The capsid maturation process of the Nudaurelia capensis omega virus includes pH-dependant conformational changes and auto-proteolysis. Like many human viruses such as HIV and herpes virus, NwV, an insect virus, requires these specific structural changes to become infectious.