credimus in 7TMR

Crystal structure of the β2 adrenergic receptor–Gs protein complex
Søren G. F. Rasmussen et. al.
Nature (2011) doi:10.1038/nature10361

Mirum!

Antibody & Nanobdy

*Image courtesy of David Goodsell and PDB

scientia artis.

Whoever says scientists lack aesthetic creativity is seriously misinformed.

macrophage and bacterium 2,000,000x

Watercolor, David Goodsell 2002

Bacillaceae pulcher

A beautiful toxin

Ribbon model of botulinum toxin serotype A (1).

The botulinum neurotoxin blocks signal transduction from occuring in motor neurons. The toxin causes flaccid paralysis by cleaving SNARE proteins that function in synaptic vesicle exocytosis. The toxin is produced by numerous species of Clostridium, most notable Clostridium botulinum. The toxic protein is expressed as a single chain 150kDa protein, which is cleaved into dichain proteins and bound by a disulfide bond with AB structure function properties. The N-terminal A domain measures nearly 50 kDa and functions as zinc metalloprotease. The C-terminal or B domain is approximately 100 kDa and is composed of two functional domains, which are involved in receptor recognition and translocation of the A domain across the endosomal membrane. The N-terminal or A domain is also classified as the Light Chain. The LC’s function as a mettalloprotease attacks fusion proteins (SNAP-25, syntaxin or synaptobrevin) at the neuromuscular junction, preventing vesicles from fusing with the membrane and releasing acetylcholine (2,3).

Acetylcholine is an important neurotransmitter, which when bound to acetylcholine receptors on skeletal muscles, opens ligand gated sodium channels in the cell membrane. The Sodium ions enter the muscle cell and stimulate muscle contraction. Therefore, the cleavage of fusion proteins by the botulinum toxin inhibits the vesicles from binding to the acetylcholine receptors causing flaccid paralysis.

Fig. A. Model of binding of type B botulinum neurotoxin via both Syt-II and ganglioside receptors at the presynaptic membrane. The cytoplasm domain of synaptotagmin is presented as 2 C2 domains (light pink) bound with calcium ions (yellow spheres), modeled by 1TJX and 1DQV (4).*

Fig. B. Overview of type A1 botulinum neurotoxin (yellow) in complex with the CR1 antibody (antibody heavy and light chains in magenta and green, respectively)(5).*

**Above descriptions were taken from The Stevens Laboratory at The Scripps Research Institute, La Jolla, CA (6).

1. 3D ribbon model of botulinum neurotoxin serotype A (botox) from PDB 3BTA. Ref.: Lacy, D.B., Tepp, W., Cohen, A.C., DasGupta, B.R., Stevens, R.C. (1998) Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat.Struct.Biol. 5: 898-902
2. Foran PG, Mohammed N, Lisk GO, et al. (2003). "Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons". J. Biol. Chem. 278 (2): 1363–71.
3. Kukreja R, Singh BR (2009). "Botulinum Neurotoxins: Structure and Mechanism of Action". Microbial Toxins: Current Research and Future Trends. Caister Academic Press
4. Reprinted from Chai, Q., Arndt, J.W., Dong, M., Tepp, W.H., Johnson, E.A., Chapman, E.R., Stevens, R.C. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 444:1096, 2006.
5.Reprinted from Garcia-Rodriguez, C., Levy, R., Arndt, J.W., Forsyth, C.M., Razai, A., Lou, J., Geren, I., Stevens, R.C., Marks, J.D. Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin. Nat. Biotechnol. 25:107, 2007.
6. http://stevens.scripps.edu/BoNT.html

Nova methodus integrandi inhibere

HIV-1 Integrase

HIV-1 integrase (IN) is encoded by HIV gag-pol gene and has recently gained interest as the newest target for anti-retroviral therapy. HAART has been used to treat HIV since the development of protease inhibitors in the mid- 1990s. Since then the mortality rate associated with HIV has dropped nearly four fold for those who use HAART. While the drug cocktail consisting of protease inhibitors (PI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and nucleoside reverse transcriptase inhibitors (NRTI) has clearly proven successful in delaying the onset of AIDS, numerous side effects have been associated with the long term use of anti-retrovirals. GI upset, peripheral glucose resistance, and lipodystrophy to name a few. For most such side effects are greatly outweighed by the success of HAART. However, for some such a regiman is intolerable and for others drug-resistant variants of the virus render some drugs nearly ineffective. The newest anti-retroviral is a HIV integrase inhibitor, the first on the market being raltegravir.

HIV IN is responsible for integrating retroviral DNA into the host cell's genome. While HIV IN has yet to be crystallized in complex with DNA, the prototype foamy virus integrase has been crystallized in complex with DNA and raltegravir. Such structural data should prove valuable in future drug design and discovering characteristics of such a class of enzymes.

The above rendering was taken using (PDB ID: 3L2T) thanks to beautiful work done by Stephen Hare et al (2010). Find out more information here

Victis finem

Atomic VRC01 IgG Binding to HIV gp120

This above rendering shows the atomic structure of the antibody VRC01 (blue and green) binding to HIV (grey and red). The precise site of VRC01-HIV binding (red) is a subset of the area of viral attachment to the primary immune cells HIV infects.

Credit: NIAID VRC

fluorescens

Cartoon structure of GFP. The fluorophore structure originates from an internal Ser-Tyr-Gly sequence which is post-translationally modified to a 4-(p-hydroxybenzylidene)- imidazolidin-5-one. The fluorophore is generated by sequential auto-catalysis process. The reaction is initiated by a rapid cyclization between Ser65 and Gly67 to form an imidazolin-5-one intermediate which is followed by a much slower rate-limiting oxygenation of the Tyr66 side chain by O₂ on a timescale of hours. Gly67 is required for formation of the fluorophore, no other amino acid can replace Gly in this role.

For more detail regarding the mechanism of GFP and GFP derivatives check out this paper:

http://www.pnas.org/content/100/21/12111.full