The Biologically Relevant Unit and Crystal Packing

One also needs to consider whether the structural model is in the appropriate mechanistic state. Some targets (e.g., nuclear hormone receptor), can exist either in active or in inactive state. One can wish to design either antagonists or agonists for such targets. The appropriate state for use in vHTS depends on the mode of action desired. 

A common mechanism of regulating the state of a protein is via phosphorylation/ dephosphorylation (by kinases and phosphatases, respectively). Serine and threonine residues are the most commonly phosphorylated residues. Tyrosine residues can also be phosphorylated as can histidines. Other mechanisms of controlling the state of proteins include sulfonation and methylation (by sulfotransferases and methyltrans-ferases, respectively). Such posttranslational modifications to the protein are key to the behavior of the target in question and a vHTS study should target the state of interest. One should also be wary of engineered proteins, where one or more residues may have been mutated to alter the biological behavior of said protein. 

Some deposited structures in the PDB, such as binding proteins, may only represent part of the story. The biologically relevant unit may, in fact, be an aggregate of more than one chemically distinct structural domain the crystal structure in the PDB may represent only one of these domains. An example is the set of matrix metalloproteinases (MMP) structures. Some MMPs are bound to hemopoxin moi- 

REMARK 300 REMARK 300 REMARK 300 REMARK 300 REMARK 350 REMARK REMARK REMARK REMARK REMARK REMARK REMARK REMARK 

THIS ENTRY CONTAINS THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT WHICH CONSISTS OF 1 CHAIN (S). SEE REMARK 350 FOR INFORMATION ON GENERATING THE BIOLOGICAL MOLECULE (S).  

---