Structural Proteomics: Inferring Function from Protein Structure

Abstract

We describe how knowledge of three dimensional protein structure can add to the understanding of as yet functionally unannotated protein sequences. Structure determination may reveal that the new protein shares structural similarity with a previously observed structure or that it is a novel fold. The manner in which structure can be used to suggest the function of a protein will depend on the number and diversity of homologous sequences and the extent to which these sequences are functionally characterized. These factors are discussed with reference to a number of illustrative examples of structures solved by structural genomics initiatives.

Protein Function Prediction Using Local 3D Templates

“…A number of reviews have been written describing these, and other, methods for predicting function from structure. [5][6][7][8] Not all methods are successful, or indeed helpful, in all cases, as is evident from the fact that around 35% of the structural genomics structures are still annotated as hypothetical proteins. Thus, there is plenty of scope for new methods to complement those already in use.…”

Proteomics in human cancer research

“…To address this issue, large-scale protein structure determination projects have been initiated in several laboratories [74,75]. These initiatives which are referred to as "structural proteomics" is initiated because protein 3-D structure is more conserved than DNA sequence and this opens up the possibility of biochemical or biophysical functional characterization via structure [76]. An early success of the structural proteomics initiative was the elucidation of the crystal structure of a functionally unannotated protein, MJ0577, from Methanococcus jannaschii by Zarembinski et al [77].…”

“…Elucidating the structure of proteins can also reveal unique sites for binding, interaction, catalysis, and allosteric regulation. It is believed that the availability of three dimensional protein crystal structures and structures obtained by modeling, in addition to better computing power, will allow the dynamics and function of proteins to be better investigated [76,78]. X-ray crystallography is still the most powerful method for protein structure determination.…”

The reductionist paradox: are the laws of chemistry and physics sufficient for the discovery of new drugs?

“…1. On the ''Reductionist'' side of the figure, dramatic increases in the capabilities of molecular, cellular, and structural biology have enabled us to elucidate the structural details of a growing number of macromolecular entities until we are now able to solve the structure of proteins with no known function(s) [1]. However, as we move down the hierarchy much of the biological environment within which these entities function is ''edited'' out.…”

“…In contrast, research expenditures have risen sharply from 10 to around 40 million USD [2]. 1 On the functionalist side of Fig. 1, moving up the biological hierarchy, function is ''reintroduced'' and the size and complexity of the systems tend to increase.…”