4n19
Structural basis of conformational transitions in the active site and 80 s loop in the FK506 binding protein FKBP12
Structural highlights
FunctionFKB1A_HUMAN Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.[1] [2] Publication Abstract from PubMedThe extensive set of NMR resonance doublings exhibited by the immunophilin FKBP12 arises from a slow transition to the cis-peptide configuration at Gly 89 near the tip of the 80's loop, site for numerous protein recognition interactions for both FKBP12 and other FKBP domain proteins. The 80's loop also exhibits linebroadening, indicative of mus-ms conformational dynamics, but only in the trans-peptide state. The G89A variant shifts the trans-cis peptide equilibrium from 88:12 to 33:67, while the proline substitution fully induces the cis-peptide configuration. The 80's loop conformation in the G89P crystal structure at 1.50 A resolution differs from wild type FKBP12 primarily for residues 88, 89 and 90, and it closely resembles that reported for FKBP52. Structure-based chemical shift predictions indicate that the mus-ms dynamics in the 80's loop likely arise from a concerted mainchain (psi88, phi89) torsion angle transition. The indole sidechain of Trp 59 at the base of the active site cleft is reoriented ~90o and the adjacent backbone is shifted in the G89P crystal structure. NOE analysis of wild type FKBP12 demonstrates that this indole populates the perpendicular orientation at 20%. 15N relaxation analysis is consistent with the indole reorientation occurring in the ns timeframe. Recollection of the G89P crystal data at 1.20 A resolution reveals a weaker wild type-like orientation for the indole ring. Differences in the residues that underlie the Trp 59 indole ring and altered interactions linking the 50's loop to the active site suggest that reorientation of this ring may be disfavored in the other six members of the FKBP domain family that bear this active site tryptophan. Structural basis of conformational transitions in the active site and 80's loop in the FK506 binding protein FKBP12.,Mustafi SM, Brecher M, Zhang J, Li H, Lemaster DM, Hernandez G Biochem J. 2014 Jan 10. PMID:24405377[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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