7a6x | pdb_00007a6x

Structure of the FKBP51FK1 domain in complex with the macrocyclic SAFit analogue 56

spinqualitylabelsall models 7a6x, resolution 1.67Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7a6x is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: R3B Gene: FKBP5, AIG6, FKBP51 (HUMAN) Activity: Peptidylprolyl isomerase, with EC number 5.2.1.8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [FKBP5_HUMAN] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. Publication Abstract from PubMed The FK506-binding protein 51 (FKBP51) emerged as a key player in several diseases like stress-related disorders, chronic pain, and obesity. Linear analogues of FK506 called SAFit were shown to be highly selective for FKBP51 over its closest homologue FKBP52, allowing the proof-of-concept studies in animal models. Here, we designed and synthesized the first macrocyclic FKBP51-selective ligands to stabilize the active conformation. All macrocycles retained full FKBP51 affinity and selectivity over FKBP52 and the incorporation of polar functionalities further enhanced affinity. Six high-resolution crystal structures of macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode. Our results show that macrocyclization is a viable strategy to target the shallow FKBP51 binding site selectively. Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors.,Bauder M, Meyners C, Purder PL, Merz S, Sugiarto WO, Voll AM, Heymann T, Hausch F J Med Chem. 2021 Mar 5. doi: 10.1021/acs.jmedchem.0c02195. PMID:33666419 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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