4jfi

Increasing the Efficiency Efficiency of Ligands for the FK506-Binding Protein 51 by Conformational Control: Complex of FKBP51 with compound 1-[(9S,13R,13aR)-1,3-dimethoxy-8-oxo-5,8,9,10,11,12,13,13a-octahydro-6H-9,13-epiminoazocino[2,1-a]isoquinolin-14-yl]-2-(3,4,5-trimethoxyphenyl)ethane-1,2-dioneIncreasing the Efficiency Efficiency of Ligands for the FK506-Binding Protein 51 by Conformational Control: Complex of FKBP51 with compound 1-[(9S,13R,13aR)-1,3-dimethoxy-8-oxo-5,8,9,10,11,12,13,13a-octahydro-6H-9,13-epiminoazocino[2,1-a]isoquinolin-14-yl]-2-(3,4,5-trimethoxyphenyl)ethane-1,2-dione

Structural highlights 4jfi is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , Related: 4jfj, 4jfk, 4jfl, 4jfm Gene: AIG6, FKBP5, FKBP51 (Homo sapiens) Activity: Peptidylprolyl isomerase, with EC number 5.2.1.8 Resources: FirstGlance, OCA, RCSB, PDBsum Function [FKBP5_HUMAN] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. Publication Abstract from PubMed The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr(113) that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51. Increasing the efficiency of ligands for FK506-binding protein 51 by conformational control.,Wang Y, Kirschner A, Fabian AK, Gopalakrishnan R, Kress C, Hoogeland B, Koch U, Kozany C, Bracher A, Hausch F J Med Chem. 2013 May 23;56(10):3922-35. doi: 10.1021/jm400087k. Epub 2013 May 6. PMID:23647266 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also FK506 binding protein

spinqualitylabelsall models 4jfi, resolution 1.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image