Biological macromolecules, such as proteins and DNA, are very small and very complex. It is something of a technological miracle, therefore, that we can visualise their three-dimensional structures at atomic resolution. The first, and still by far the dominant, method of solving these structures is crystallography.
The principal is simple: by packing many millions of molecules into a repeating crystal lattice, the diffraction pattern of X-rays passing through the crystal captures information about the structure of the individual molecules. In effect, the structural information from many identical molecules amplifies the signal to the point where it can be read and decoded.
This ability to see the structures of individual protein molecules was a huge breakthrough in biology. It may not be as famous as the DNA double helix, but the first protein structure, earned a Nobel prize for Max Perutz in 1962, the same year that Watson, Crick and Wilkins were honoured for solving the DNA structure by the same crystallographic technique.
In the intervening six decades, many thousands of protein structures have been solved in this way, and delivered mechanistic insight into the many functions of proteins, as structural components, molecular motors, enzymes, synthetic factories and signalling networks. They have underpinned the development of numerous drugs, designed to bind in highly specific ways to particular proteins. Today, variations on a theme even allow us to visualise structures of membrane-bound proteins that traditionally eluded crystallisation.
So great has been the positive impact of having a window on these ultra-microscopic structures that its hard to imagine that the ubiquitous application of crystallography has had a unintended negative consequence for our understanding of biology.
Structures obtained using these methods that average across millions of molecules are so embedded in our thinking that we accept them as representative of the protein in vivo, almost without thinking, and certainly without constantly bearing in mind the single biggest assumption of crystallography: that all the molecules are the same.
Together with the cult of DNA centricity, this cult of crystallography has led to a very distorted view of what we think of as a protein. When we name a protein, such as apolipoprotein E (one of DrugBaron’s favorite proteins), the implicit assumption is that we refer to a homogeneous population of molecules, all with the same primary sequence (that is, the same amino acid building blocks in the same order, exactly as encoded by the DNA sequence of the apoE gene) and all with the same three-dimensional structure and conformation …
RxCelerate Ltd is an outsourced drug development platform based near Cambridge, UK. We specialize in delivering an entire road map of drug development services from discovery and medicinal chemistry through to formal preclinical development and clinical up to Phase IIa. In the last five years, we have witnessed dramatic changes in the drug development …