Conclusions

With the increased number of new protein sequences obtained by genomic and proteomic efforts, a high-throughput and widely applicable protein structure analysis technology such as DXMS is needed. Recent improvements of MS instrumentation, fluidics, automation, fragmentation chemistry, and data analysis software have made this technology sensitive, robust, high-throughput, and capable of achieving near single-amide resolution. Examples cited here demonstrate that DXMS has exceptional potential to facilitate many steps of the drug discovery process. First, DXMS can guide construct optimization to speed X-ray crystallo-graphic structure determination. Second, the nature of binding sites and binding-induced conformational changes can be determined for the target protein with DXMS. Third, the unique high-resolution thermodynamic information provided by DXMS allows the focusing of discovery efforts to evolutionarily selected binding hot spots in what otherwise appear to be bland protein-protein binding surfaces. Finally, DXMS can be very useful in the characterization and quality control of whole protein therapeutics.

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