3 7 I H I G H L I G H T S 2 0 2 1
Similar to previous SAFit ligands, binding of macrocyclic analogues resulted in an outward flip of FKBP51 residue phenylalanine 67, which enables the selectivity against FKBP52. However, for the macrocyclic SAFit analogues, several additional conformational changes were observed. Most prominent is that a small beta strand is rearranged,
resulting in a displacement of aspartic acid 68 and serine 70 and a compensatory inward flip of histidine 71 to stack against Tyr57. Interestingly, histidine 71 is replaced by the larger residue arginine in the sequences of FKBP12 and FKBP12.6, providing a molecular rationale for the observed selectivity profile of the macrocyclic SAFit analogues.
PRINCIPAL PUBLICATION AND AUTHORS
Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity, A.M. Voll (a), C. Meyners (a), M.C. Taubert (a), T. Bajaj (b), T. Heymann (a), S. Merz (a), A. Charalampidou (a), J. Kolos (a), P.L. Purder (a), T.M. Geiger (a), P. Wessig (c), N.C. Gassen (b), A. Bracher (d), F. Hausch (a), Angew. Chem. Int. Ed. 60, 13257-13263 (2021); https:/doi.org/10.1002/anie.202017352 (a) Technical University Darmstadt, Darmstadt (Germany) (b) University of Bonn, Bonn (Germany) (c) University of Potsdam, Potsdam (Germany) (d) Max Planck Institute of Biochemistry, Martinsried (Germany)
 P.K.A. Jagtap et al., Angew. Chem. Int. Ed. 58, 9429-9433 (2019).  S. Gaali et al., Nat. Chem. Biol. 11, 231-240 (2015).  M. Bauder et al., J. Med. Chem. 64, 3320-3349 (2021).  A.M. Voll et al., Angew. Chem. Int. Ed. 60, 13257- 13263 (2021).
Structural understanding of chronic lymphocytic leukaemia subsets for BcR-targeting personalised treatments
The malignant B-lymphocytes in chronic lymphocytic leukaemia (CLL) proliferate autonomously because of self-induced signals. A visualisation of the structural details of the contacts between receptors that activate the pathogenic B-cells is crucial for understanding the diversity of the outcome of CLL in patients, and guiding the development of personalised treatments.
Chronic lymphocytic leukaemia (CLL) is the most common blood malignancy in western countries, and is characterised by the accumulation of mature B-lymphocytes with a characteristic immunophenotype, but extremely diverse clinical manifestations . B-cell receptor immunoglobulins (BcRs) from CLL patients can, however, be grouped into subsets based on homology in the heavy chain complementarity-determining region 3 (HCDR3), and patients within a given CLL subset share other immunogenetic features and similar clinical outcomes. The high homology in BcRs within subsets consolidates the role of antigen(s) in the selection of the
Fig. 23: Structure and contacts between CLL-derived Fabs. The protein surfaces along with the cartoon representation are shown; heavy and light chains are coloured blue and pink, respectively. Variable and constant domains of Fab are labelled for clarity (VH, VL: variable domains of heavy or light chain; CH, CL: constant domains of heavy or light chain), and shown as cartoon.