Among the 22 FKBP domains in the human genome, FKBP12.6 and the first FKBP domains
(FK1) of FKBP51 and FKBP52 are evolutionarily and structurally most similar to the archetypical
FKBP12. As such, the development of inhibitors with selectivity among these four FKBP domains
poses a significant challenge for structure-based design. The pleiotropic effects of these FKBP
domains in a range of signaling processes such as the regulation of ryanodine receptor calcium channels
by FKBP12 and FKBP12.6 and steroid receptor regulation by the FK1 domains of FKBP51 and FKBP52 amply justify
the efforts to develop selective therapies. In contrast to their close structural similarities, these four FKBP domains
exhibit a substantial diversity in their conformational flexibility. A number of distinct conformational transitions have
been characterized for FKBP12 spanning timeframes from 20 s to 10 ns and in each case these dynamics have been shown
to markedly differ from the conformational behavior for one or more of the other three FKBP domains. Protein flexibilitybased
inhibitor design could draw upon the transitions that are significantly populated in only one of the targeted proteins.
Both the similarities and differences among these four proteins valuably inform the understanding of how dynamical effects
propagate across the FKBP domains as well as potentially how such intramolecular transitions might couple to the
larger scale transitions that are central to the signaling complexes in which these FKBP domains function.
Keywords: Allostery, conformational dynamics, crystallography, FKBP domain, NMR.
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