From information management to protein annotation: preparing protein structures for drug discovery

Abstract

In contrast to academic pursuits of structural genomics, Structural GenomiX (SGX) solves protein structures at high throughput for the main purpose of enhancing drug-discovery projects, either internally or in partnership with pharmaceutical/biotechnology companies. This involves a radical redesign of the pipeline of methods that turn a gene sequence into a three-dimensional protein structure. The various processes all report electronically to a Laboratory Information Management System (LIMS) to make sure all the parameters of the experiment are recorded in an accessible and`mineable' form, helping guarantee reproducibility of results. Quality control at several key points keeps the process from branching out on a wrong hypothesis. Protein annotation, in a broad sense, takes care of the interpretation of a protein crystal structure or the crystal structure of one or several protein± ligand complexes. This interpretation both gathers all necessary biological information (protein function, mechanism, speci®c features within a protein family etc.) and hands over this information in a form accessible to medicinal chemistry teams designing speci®c small-molecule agonists or antagonists.

Quality of protein crystal structures

“…In addition to proprietary structural studies performed by pharmaceutical companies, various structural genomics projects have been initiated (Peat et al, 2002;Geerlof et al, 2006;Rupp et al, 2002;Liu et al, 2005). 18 structural genomics centers currently exist and have deposited over 2000 structures in the Protein Data Bank.…”

The open-access high-throughput crystallization facility at EMBL Hamburg

“…As a consequence, the process of biological crystallization has been heavily automated in order to increase both its success rate by minimizing the amount of sample per experiment (Chayen et al, 1994;DeLucas et al, 2003) and its time efficiency by parallelizing the process of experiment setup (Krupka et al, 2002;Hazes & Price, 2005). These efforts have resulted in the establishment of several academic (Heinemann et al, 2000;Watanabe et al, 2002;Albeck et al, 2005) and industrial high-throughput facilities (Peat et al, 2002;Hosfield et al, 2003). However, there are only a few academic laboratories worldwide that offer access to such a facility to the general user community (Luft et al, 2003).…”

Challenges in the Overall Analysis of Microbial Proteomes

“…Despite these difficulties, LIMS systems are beginning to be introduced in processes with well-defi ned workfl ows. For example, a LIMS system is used to follow the entire process during protein structure elucidation using crystallography [85] . A LIMS system was also used to track the starting sample, the various sample fractionation steps, the MS data and the protein identifi cation results, in a large-scale proteomics study of human plasma [86] .…”