De novo phasing with X-ray laser reveals mosquito larvicide BinAB structure

Publication in Nature, view here

Abstract

BinAB is a naturally occurring paracrystalline larvicide distributed worldwide to combat the devastating diseases borne by mosquitoes. These crystals are composed of homologous molecules, BinA and BinB, which play distinct roles in the multi-step intoxication process, transforming from harmless, robust crystals, to soluble protoxin heterodimers, to internalized mature toxin, and finally to toxic oligomeric pores. The small size of the crystals—50 unit cells per edge, on average—has impeded structural characterization by conventional means. Here we report the structure of Lysinibacillus sphaericus BinAB solved de novo by serial-femtosecond crystallography at an X-ray free-electron laser. The structure reveals tyrosine- and carboxylate-mediated contacts acting as pH switches to release soluble protoxin in the alkaline larval midgut. An enormous heterodimeric interface appears to be responsible for anchoring BinA to receptor-bound BinB for co-internalization. Remarkably, this interface is largely composed of propeptides, suggesting that proteolytic maturation would trigger dissociation of the heterodimer and progression to pore formation.

 

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UCLA-DOE PI’s visit the Pacific Northwest National Laboratory

UCLA-DOE PI’s visit the Pacific Northwest National Laboratory to team up on new research projects involving state-of-the-art scientific instrumentation.

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Eisenberg lab produces Ab Initio protein structure from prion nanocrystals at atomic resolution by MicroED

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We illustrate a method to access the long unrealized potential of
electrons in the crystallographic structural determination of
biological molecules. Electrons, owing to their strong interaction
with matter, produce high resolution diffraction patterns from tiny
three-dimensional biomolecular crystals (MicroED), enticing structural
biologists with a means to gain much needed insight into the detailed
workings of biological systems and disease mechanisms. However,
barriers to successful use of MicroED arise from a phenomenon known as
dynamical scattering and lack of a means of recovering phases from
diffracted electrons. We showed that if the diffraction resolution is
high enough and the crystals are sufficiently small, both barriers are
overcome, unlocking the potential of MicroED for elucidation of novel
biomolecules.

Click here for: PNAS Full Article

 

Todd Yeates work highlighted in Science


Todd Yeates lab published in Science and highlighted on the cover:

Accurate design of megadalton-scale two-component icosahedral protein complexes.

Included is a Video from Science

Abstract
Nature provides many examples of self- and co-assembling protein-based molecular machines, including icosahedral protein cages that serve as scaffolds, enzymes, and compartments for essential biochemical reactions and icosahedral virus capsids, which encapsidate and protect viral genomes and mediate entry into host cells. Inspired by these natural materials, we report the computational design and experimental characterization of co-assembling, two-component, 120-subunit icosahedral protein nanostructures with molecular weights (1.8 to 2.8 megadaltons) and dimensions (24 to 40 nanometers in diameter) comparable to those of small viral capsids. Electron microscopy, small-angle x-ray scattering, and x-ray crystallography show that 10 designs spanning three distinct icosahedral architectures form materials closely matching the design models. In vitro assembly of icosahedral complexes from independently purified components occurs rapidly, at rates comparable to those of viral capsids, and enables controlled packaging of molecular cargo through charge complementarity. The ability to design megadalton-scale materials with atomic-level accuracy and controllable assembly opens the door to a new generation of genetically programmable protein-based molecular machines.

UCLA CORES

UCLA Core Technology Centers have created a new database of campus resources at http://www.cores.ucla.edu/

The site contains descriptions and contact information for each core, as well as a new searchable database of services and instrumentation (courtesy of the UCLA-DOE Institute Bioinformatics and Computational Core Technology Center).

UCLA Scientists Test New Strategy That Could Help Fight Ovarian Cancer

 

Approach borrows from technique of inhibiting protein fibers that cause Alzheimer’s and Parkinson’s diseases
* High-grade serous ovarian cancers are aggressive tumors, and most patients relapse despite standard therapy
* UCLA researchers developed a peptide that penetrates cancer cells and stops their growth by restoring the protective function of the p53 protein
* Scientists hope to test this therapeutic approach to treat women with ovarian cancer in the near future

UCLA scientists have developed a promising novel method to treat gynecologic tumors. The approach focuses on a protein called p53, which is commonly mutated in women who have high-grade serous ovarian cancer, the deadliest form of reproductive cancer. In many women with the disease, the cancer is very advanced by the time it is diagnosed and is therefore difficult to treat.

Read more

Uncovering the Mechanism of Aggregation of Human Transthyretin

Published in the Journal of Biological Chemistry, the work of Dr. Lorena Saelices and coworkers under the supervision of Prof. David Eisenberg establishes a novel therapeutic strategy for transthyretin amyloidosis. The team identified two segments of transthyretin that are responsible for the protein aggregation and determined the structure of their fibrils. The fibril structures were used to design peptide inhibitors that block self-association of the two segments, and hinder transthyretin amyloid formation. The research published in December, 2015 opens a new approach to tackle the life-threatening transthyretin amyloidosis.

Abstract of the manuscript:

The tetrameric thyroxine-transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of transthyretin has been reported as the cause of the life-threatening transthyretin amyloidosis. The standard treatment of familial cases of TTR amyloidosis has been liver transplantation. Although aggregation-preventing strategies involving ligands are known, understanding the mechanism of TTR aggregation can lead to additional inhibition approaches. Several models of TTR amyloid fibrils have been proposed, but the segments that drive aggregation of the protein have remained unknown. Here we identify beta-strands F and H as necessary for TTR aggregation. Based on the crystal structures of these segments, we designed two non-natural peptide inhibitors that block aggregation. This work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy

 

Professor David Eisenberg was awarded the Legacy Award at the 2nd Annual UCLA Molecular Biology Institute (MBI) Awards Dinner on November 12th.

MBI Awards Dinner small
The Legacy Award honors outstanding MBI faculty mentors who have worked to inspire, encourage and guide the next generation of scientists and thought leaders.Professor Eisenberg is a Distinguished Professor of Chemistry and Biochemistry and of Biological Chemistry, an HHMI investigator, and the inaugural Chair Holder of the Paul D. Boyer Professorship in Molecular Biology Biochemistry. He served as director of the UCLA-DOE Institute for Genomics and Proteomics from 1993 to 2014.

Nobel Laureate and founding MBI Director Paul D. Boyer and Lyda Boyer attended the event which was held at the UCLA Hershey Hall Grand Salon.

Professor David Eisenberg was presented the Legacy Award by MBI Director Professor Luisa Iruela-Arispe.

Professor David Eisenberg was presented the Legacy Award by MBI Director Professor Luisa Iruela-Arispe.

Left to right: Lyda Boyer, Professor Paul Boyer, and Lucy Eisenberg.

Left to right: Lyda Boyer, Professor Paul Boyer, and Lucy Eisenberg.

Members of Prof. Eisenberg's group pose for a photo at the event (left to right): Dr. Nicole Wheatley, Dr. Alice Soragni, Dr. Lorena Saelices, Jeannette Bowler, Dr. Rebecca Nelson, Pascal Krotee, Prof. David Eisenberg, Elizabeth Guenther, Sarah Griner, Shannon Essewein, and assistant Cindy Chau.

Members of Prof. Eisenberg’s group pose for a photo at the event (left to right): Dr. Nicole Wheatley, Dr. Alice Soragni, Dr. Lorena Saelices, Jeannette Bowler, Dr. Rebecca Nelson, Pascal Krotee, Prof. David Eisenberg, Elizabeth Guenther, Sarah Griner, Shannon Essewein, and assistant Cindy Chau.

Left to right: Professor Sabeeha Merchant (Chemistry & Biochemistry), Professor Edward De Robertis and Ana De Robertis (Biological Chemistry).

Left to right: Professor Sabeeha Merchant (Chemistry & Biochemistry), Professor Edward De Robertis and Ana De Robertis (Biological Chemistry).

2015 Postdoctoral Awardees

Three Postdocs from MBI Labs were recipients of the 2015 Postdoc Awards.

  • Crysten Blaby from the Merchant lab
  • Luz Orozco from the Pellegrini lab
  • Jose Rodriguez from the Eisenberg lab

The events was held on Oct. 9th at the California NanoSystems Institute (CNSI).

PostDoc Awards 151009

PostDoc Awards 2015

More information can be found here

 

Jose Rodriguez and Luz Orozco

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Crysten Blaby

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Jose Rodriguez receives Post-Doctoral award 10/8/2015

Jose Rodriguez receives 2015 Postdoctoral Recognition Award. From Left: Phyllis Parvin, Jose Rodriguez, Paul Boyer and David Eisenberg .