Protein structural biology

Proteins are a functionally diverse class of macromolecule that underpin every biological process. They are by far the most common therapeutic target - a 2017 review of FDA-approved drugs listed 1194 entries directed towards 667 unique human protein targets, compared to 220 drugs targeting pathogen proteins and 177 targeting other human or pathogen biomolecules ⁽¹⁾.

Made from a chain of amino acids (of which 22 different kinds can be found in the human body), more than 100,000 unique proteins are encoded by approximately 20,000 different genes. Proteins are required for the replication and transcription of DNA, and the production, processing and transport of other proteins; they act as enzymes, chaperones, transporters, receptors, ion channels and can form specialized structural landmarks unique to particular cells or tissues; they control cell division, cell metabolism and a host of intracellular and extracellular biochemical pathways.

Knowledge of the three-dimensional structure of proteins at atomic level gained through X-ray crystallography, Cryo-EM and NMR, has contributed hugely to our understanding of this functional diversity. The structural scaffold outlined from the secondary/tertiary features creates unique binding sites where other proteins or ligands can reversibly interact. Subunits from a closely-related family of proteins can combine in a variety of quaternary structures to give rise to even further functional variation. These structures are often flexible, and capable of reversible conformational changes in order to mediate their particular cellular processes. The expression of particular proteins, or variants from the same protein family, can also be highly tissue-specific.

This breadth of protein form, function and expression gives almost infinite scope for the design of new therapeutic agents that can functionally-modulate these molecules. And our developing capability in analysing structure, protein-protein interactions, protein-ligand binding sites and understanding ‘drugability’ gives us a great place from which start.

At SDDC, we use a variety of tools to inform our early-stage drug discovery. Among them, isolation, production and enabling of active protein targets for high-throughput screening assays against compound libraries, and elucidation of three-dimensional structures of apo- (polypeptide alone) and holo- (conjugated polypeptide) forms of proteins by X-ray crystallography and/or Cryo-EM. We also conduct high-throughput structure-based fragment screening (liaising with Diamond Light Source Ltd, Oxford) which can reveal the druggable features/sites of protein targets where new drugs might bind and interact. In addition, bioinformatics-based sequence and structure-based tools (sequence analysis, homology modeling, docking) are used to investigate the protein and protein-ligand interactions in detail. Access to various cellular biochemical and biophysical assays in SDDC then helps us to progress from target identification and engagement towards a mechanistic understanding of protein binding in their respective molecular pathways.

1. Santos R, Ursu O, Gaulton A, Bento AP, Donadi RS, Bologa CG, Karlsson A, Al-Lazikani B, Hersey A, Oprea TI, Overington JP. A comprehensive map of molecular drug targets. Nat Rev Drug Discov 16: 19, 2017. doi: 10.1038/NRD.2016.230.