A detailed understanding of the functions and interactions of biological macromolecules requires knowledge of their molecular structures. Structural genomics, the systematic determination of all macromolecular structures represented in a genome, is focused at present exclusively on proteins. It is clear, however, that RNA molecules play a variety of significant roles in cells, including protein synthesis and targeting, many forms of RNA processing and splicing, RNA editing and modification, and chromosome end maintenance. To comprehensively understand the biology of a cell, it will ultimately be necessary to know the identity of all encoded RNAs, the molecules with which they interact and the molecular structures of these complexes. This report focuses on the feasibility of structural genomics of RNA, approaches to determining RNA structures and the potential usefulness of an RNA structural database for both predicting folds and deciphering biological functions of RNA molecules.
An important aspect of structural genomics is connecting coordinate data with whole-genome information related to phylogenetic occurrence, protein function, gene expression, and protein-protein interactions. Integrative database analysis allows one to survey the 'finite parts list' of protein folds from many perspectives, highlighting certain folds and structural features that stand out in particular ways.
Structure-based biological discovery is entering a new era with the development of industrialized macromolecular structure determination pipelines. Intense, highly focused X-rays from integrated synchrotron radiation beam lines combined with significant advances in protein expression, purification, and micro-crystallization automation allow for the full streamlining of the traditionally tedious and time consuming process of determining the three dimensional structures of macromolecules.
Commercial efforts in structural genomics focus on providing to pharmaceutical customers information that relates to the suitability of specific proteins as drug targets and the informed selection and refinement of lead compounds generated by high-throughput screening and rational approaches. These efforts follow a variety of business models and are impacted by activities in the public domain, recent technological advances, and the changing intellectual property landscape.
A group of multinational companies, together with the Wellcome Trust, is attempting to form a charitable organization, the Structural Genomics Consortium. The goal will be to obtain X-ray structures for a broad representation across families of human proteins and to place the structural coordinates in the public database.
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