May 20, 2007

2007 Week 20: Proteins


Columbia scientists determine 3-dimensional structure of cell's 'fuel gauge'
Researchers at Columbia University Medical Center have uncovered the complex structure of a protein that serves as a central energy gauge for cells, providing crucial details about the molecule necessary for developing useful new therapies for diabetes and possibly obesity. A paper published online today in the journal Science details this structure, helping to explain one of the cell's most basic and critical processes.

Electrons travel through proteins like urban commuters
For Duke University theoretical chemist David Beratan, the results of his 15 years of studying how electrons make their way through some important protein molecules can be summed up with an analogy: how do big city dwellers get from here to there?
In the Friday, Feb. 2, issue of the journal Science, Beratan and two co-authors use similar logic to describe their unified description of electron movements through certain "electron-transfer" proteins that lie at the heart of many processes essential for life. Such processes include harvesting light in photosynthesis in plant cells and generating energy in animal cells. "I think we have discovered the physical framework for thinking about all such protein electron-transfer chemistry," Beratan said. "Having this rule book in place will let scientists pose some hard but interesting questions about evolutionary pressures on protein structures.

Indel-based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor-1
We propose a novel strategy for selective targeting of essential pathogen proteins that contain sizable indels (insertions/deletions) in their sequences compared with their host orthologues. This approach has been tested on elongation factor-1[alpha] (EF-1[alpha]) from the protozoan pathogen Leishmania donovani. Leishmania EF-1[alpha] is 82% identical to the corresponding human orthologue, but possesses a 12 aminoacid sequence deletion compared with human EF-1[alpha]. We used this indel-differentiated region to design small molecules that selectively bind to leishmania EF-1[alpha] and not to the human protein. Three unrelated molecules were identified with the capacity to inhibit protein synthesis in leishmania by up to 75% while exhibiting no effect on human protein translation. These candidates may serve as prototypes for future development of antiprotozoan therapeutics. More generally, these findings provide a basis for a novel drug design platform. This platform targets essential pathogen proteins that are highly conserved across species, and consequently would not typically be considered to be conventional drug targets. We anticipate that such indel-directed targeting of essential proteins in microbial pathogens may help address the growing problem of antibiotic resistance.

Is glycine a surrogate for a D-amino acid in the collagen triple helix?
Collagen is the most abundant protein in animals. Every third residue in a collagen strand is a glycine with , = –70°, 175°. A recent computational study suggested that replacing these glycine residues with d-alanine or d-serine would stabilize the collagen triple helix. This hypothesis is of substantial importance, as the glycine residues in collagen constitute nearly 10% of the amino acid residues in humans. To test this hypothesis, we synthesized a series of collagen mimic peptides that contain one or more d-alanine or d-serine residues replacing the canonical glycine residues. Circular dichroism spectroscopy and thermal denaturation experiments indicated clearly that the substitution of glycine with d-alanine or d-serine greatly disfavors the formation of a triple helix. Host–guest studies also revealed that replacing a single glycine residue with d-alanine is more destabilizing than is its replacement with l-alanine, a substitution that results from a common mutation in patients with collagen-related diseases. These data indicate that the glycine residues in collagen are not a surrogate for a d-amino acid and support the notion that the main-chain torsion angles of a glycine residue in the native structure (especially, > 0°) are critical determinants for its beneficial substitution with a d-amino acid in a protein.

Protein-protein recognition and interaction hot spots in an antigen-antibody complex: Free energy decomposition identifies “efficient amino acids”
The molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method was applied to the study of the protein-protein complex between a camelid single chain variable domain (cAb-Lys3) and hen egg white lysozyme (HEL), and between cAb-Lys3 and turkey egg white lysozyme (TEL). The electrostatic energy was estimated by solving the linear Poisson-Boltzmann equation. A free energy decomposition scheme was developed to determine binding energy hot spots of each complex. The calculations identified amino acids of the antibody that make important contributions to the interaction with lysozyme. They further showed the influence of small structural variations on the energetics of binding and they showed that the antibody amino acids that make up the hot spots are organized in such a way as to mimic the lysozyme substrate. Through further analysis of the results, we define the concept of "efficient amino acids," which can provide an assessment of the binding potential of a particular hot spot interaction. This information, in turn, can be useful in the rational design of small molecules that mimic the antibody. The implications of using free energy decomposition to identify regions of a protein-protein complex that could be targeted by small molecules inhibitors are discussed.

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