While the infrastructure and organization of the EFI are inspired by the PSI, there are significant differences in their objectives, which offer unique opportunities for the EFI. Historically, the primary focus of the PSI has been on increasing the structural coverage of fold and sequence space, and the structure of any member of a particular sequence family is a suitable representative of the entire family. Consequently, all PSI targets are subjected to extensive triage, and only those sequences exhibiting highly favorable characteristics at each step of the pipeline are taken fonward for structure determination. This approach maximizes fold/sequence coverage regardless of functional importance. In contrast, the EFI is explicitly concerned with the discovery of function and thus will frequently necessitate the study of recalcitrant sequences requiring efforts that exceed those commonly expended on any individual PSI target. Accordingly, the PC and SC are positioned to implement considerable primary and secondary rescue strategies in protein purification, crystallization, data collection and structure determination in order to successfully prosecute those targets that are most informative in terms of function, mechanism and evolution. In particular, as needed and detailed below, the expert technical staff of the SC is prepared to provide extensive and expanded efforts in crystallization, data collection and structure determination. Furthermore, beyond these traditional aspects of the structure discovery pipeline, the SC will devote considerable resources to ligand identification efforts in order to 1) obtain direct functional insights, 2) aid in crystallization, and 3) maximize the utility of structures for computational ligand discovery.
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