From Protein Structure to Function with Bioinformatics.pdf

11 Function Predictions of Structural Genomics Results 285Fig. 11.4 Monomer of PDT from Staphylococcus aureus coloured by subdomain. The proposedPDT active site is located in a cleft between two subdomains, as circled on the diagramComparison of the PDT structures from Staphylococcus aureus and Chlorobiumtepidum indicated how binding of the l-phenylalanine changed the ACT dimerconformation. How these changes are propagated to the active site blocking PDTenzymatic activity is discussed in detail by Tan et al. (2008). The authors suggestthat binding of l-Phe introduces a number of major conformational changes(local and global) in PDT that modify the relative orientation of domains in thefull protein, which leads to changes in accessibility of the active site. Specifically,the movement results in a split of the large opening to the PDT extended catalyticsite at the centre of the PDT dimer into two smaller openings, resulting inreduced access to the catalytic site for prephenate and released phenylpyruvate.This example indicates how analysis of structures solved as part of a structuralgenomics initiative can have biological significance way beyond simple functionprediction.Yet another example from the MCSG involves the AF0491 protein from A. fulgidus(Savchenko et al. 2005), a homologue of the human Shwachman-Bodian-Diamond syndrome (SBDS) protein. SBDS is a rare autosomal recessive disordercaused by mutations in the SBDS gene on chromosome 7 and is characterized byabnormal pancreatic exocrine function, skeletal defects, and haematological dysfunction(Boocock et al. 2003). The structure of the AF0491 archaeal homologuewas determined and revealed a three domain protein (Fig 11.5).The C-terminal domain consists of a commonly occurring fold thus making itdifficult to infer function. However these domains are found to occur in manyRNA-binding and DNA-binding proteins. The central domain also adopts a commonfold, the winged helix-turn-helix (wHTH). The HTH domain (Aravind et al.