Following the development of various inhibitors and affinity probes that trap the protein in the adenylation or thiolation conformations, significant advances have been made in the crystallization of A domain-containing constructs. Using a bioisosteric analog of AMP, 5'-Osulfamoyl adenosines (AMS) were first developed for inhibition of NRPS systems that produced virulence factors (i.e. siderophore production in pathogens). AMS inhibitors can be extended with a variety of acyl substrates for the inhibition of any NRPS of interest once its substrate selectivity is known. Following the success of AMS inhibitors, dead-end affinity probes were developed using a 5'-(vinylsulfonylamino) adenosine (AVS) moiety. These probes covalently tether to Ppant, trapping A domains in the thiolation/substrate donation conformation. Several variations on both AMS and AVS probes have been subsequently used in crystallography to illuminate the various subtle shifts in protein structure throughout the catalytic cycle.