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Count on the snake for the promise of hidden, enticing knowledge. The reptile has lured Weizmann Institute scientists into cracking one of its most precious secrets: how snake venom gains its deadly, irreversible grip on a victim. Several Institute teams took part in the series of studies that lasted more than a decade and unfolded like a scientific detective story, recently culminating in success.
What the scientists have accomplished is equivalent to reconstructing a murder act in minutest detail. Using knowledge obtained from different fields of research, they produced a precise three-dimensional snapshot of a major snake venom toxin in the act of blocking vital communication pathways in the body - a blockage that often causes death within hours.
The potential payoff is far-reaching. One obvious outcome is the prospect of a drug for treating snakebite, a largely neglected plague. About a million people worldwide are bitten by venomous snakes every year; most deaths - an estimated 40,000 annually - occur in developing countries, where antivenom, currently the only effective remedy, is in short supply or unaffordable by the local population. Antivenom is produced by isolating antibodies from the serum of horses immunized by certain venoms. By revealing how a major snake toxin works, Weizmann Institute scientists have opened the way to developing a synthetic drug that would trap the toxin molecules, preventing them from harming the snakebite victim.
The implications of the Weizmann research, however, go far beyond treating snakebite. The snake toxin hooks up with molecules in the body at a busy place - the very spot that serves as a gateway for signals responsible for nerve-muscle communication. All our voluntary muscle movements, from furrowing the brow to high jumping, are dependent on these signals, which are transmitted by messenger molecules such as acetylcholine, released by the nerves. In fact, certain types of venom paralyze the body by blocking acetylcholine receptor molecules on the muscle, thus interrupting nerve-muscle communication.
But apart from carrying messages to the muscle, acetylcholine is also one of the most important molecules transmitting signals between nerve cells in the brain. This explains why abnormalities in the binding between acetylcholine and its receptors are involved in a multitude of both muscle and nervous system disorders, from myasthenia gravis to schizophrenia to Alzheimer's and Parkinson's diseases. The structural understanding of acetylcholine receptor's binding site obtained in the Weizmann study may therefore facilitate the development of a wide variety of therapies.
Snake-inspired sleuthing
The scientific sleuthing began in the laboratory of Prof. Sara Fuchs of the Immunology Department, who, for nearly three decades, has worked on the structure of the acetylcholine receptor and on disorders involving this receptor. In the mid-1980s she identified a tiny region of the receptor - comprising a dozen amino acids out of a total of nearly 3,000 - that was capable of binding with a major snake toxin called alpha-bungarotoxin. Next Fuchs launched an investigation to resolve a long- standing riddle: why some animals - the snakes themselves and their archenemy, the mongoose - are immune to snake venom. Her studies revealed that in both snakes and mongooses the structure of the acetylcholine receptor differs slightly from that of other animals. The difference was observed in the same tiny region that had earlier been shown to bind with alpha-bungarotoxin; apparently this small structural deviation suffices to protect the animals by preventing venom from binding. The scientists hypothesized that they had zeroed in on the receptor's binding site, its 'holy of holies.' But how could they prove this?
In the early 1990s, Fuchs teamed up with Institute Prof. Ephraim Katzir. A world-famous biochemist and one of the founders of biological research at Weizmann, Katzir later served as President of Israel and then returned to the Institute to continue his research in biological recognition. Now 85, Katzir did not balk at embarking upon a new area of study. His team member Dr. Moshe Balass, together with Fuchs, searched through a huge 'library' of peptides (protein fragments) until they identified one peptide that had a specific interaction with alpha-bungarotoxin. The result was both surprising and rewarding: The peptide corresponded to the exact spot in the acetylcholine receptor that Fuchs had marked in earlier studies as the potential binding site.
To obtain more knowledge of the binding site, Fuchs, Katzir, and Balass formed yet another collaboration - with Prof. Jacob Anglister of the Structural Biology Department and Dr. Tali Scherf, now of the Institute's Chemical Services. These studies, using nuclearmagnetic resonance (NMR)spectroscopy, revealed crucialstructural aspects of the binding between the peptide and alpha-bungarotoxin.
Details of the deadly grip
The next breakthrough occurred when a team consisting of Katzir's postdoctoral fellow Dr. Roni Kasher, Balass, Fuchs, Scherf, and Prof. Mati Fridkin of the Organic Chemistry Department took advantage of the NMR data; using sophisticated modification methods they designed a new series of peptides with an exceptionally good fit to the snake toxin. Kasher then created crystals of the peptide and the toxin, needed for an X-ray analysis. The stage was now set for a precise structural analysis of the peptide-toxin complex. Scherf used NMR to probe the complex while Prof. Joel Sussman of the Structural Biology Department, author of several landmark papers involving acetylcholine, applied X-ray crystallography. What reinforced the findings was that the structures that emerged from the two different technologies were similar.
Still the evidence regarding the location of the binding site remained circumstantial because a crucial piece of the puzzle was missing: To obtain a full picture of the toxin in action the scientists needed crystals of the entire acetylcholine receptor, which, despite numerous attempts by laboratories around the world, has not yet been crystallized. Sussman managed to provide the next best thing: he contacted Dutch colleagues who had crystallized a protein that is virtually identical to the outer portion of the acetylcholine receptor - the portion that protrudes outside the cell membrane and harbors the binding site.
The scientists could now map the atomic structure of the snake toxin blocking the acetylcholine receptor. Using X-ray crystallography, Sussman and Dr. Michal Harel of the same department revealed that the three-pronged toxin molecule wraps around acetylcholine's binding area, inserting its middle 'finger' directly into the binding site gorge. This picture explains the exact way in which the venom blocks access to acetylcholine, preventing the nerve message from reaching the muscles. Little wonder that the venom's paralyzing grip on the victim is irreversible!
The new structural knowledge obtained in this research may prove a powerful tool in developing antivenom drugs as well as in the design of therapies for disorders involving the acetylcholine receptor. While its reputation may have been tarnished by its sneaky role in Adam and Eve's banishment from the Garden of Eden, this time around, the snake seems to have more than delivered on its promise to impart valuable knowledge.
Prof. Sara Fuchs holds the Professor Sir Ernst B. Chain Chair of Neuro-Immunology.
Prof. Ephraim Katchalsky-Katzir holds the Theodore R. Racoosin Chair of Biophysics
Prof. Mati Fridkin holds the Lester B. Pearson Chair of Protein Research
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