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Review
. 2017 Nov 8;61(5):505-516.
doi: 10.1042/EBC20170041. Print 2017 Nov 8.

Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders

Scott J Hughes  1 , Alessio Ciulli  2
Affiliations
Review

Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders

Scott J Hughes et al. Essays Biochem. .

Abstract

Molecular glues and bivalent inducers of protein degradation (also known as PROTACs) represent a fascinating new modality in pharmacotherapeutics: the potential to knockdown previously thought 'undruggable' targets at sub-stoichiometric concentrations in ways not possible using conventional inhibitors. Mounting evidence suggests these chemical agents, in concert with their target proteins, can be modelled as three-body binding equilibria that can exhibit significant cooperativity as a result of specific ligand-induced molecular recognition. Despite this, many existing drug design and optimization regimens still fixate on binary target engagement, in part due to limited structural data on ternary complexes. Recent crystal structures of protein complexes mediated by degrader molecules, including the first PROTAC ternary complex, underscore the importance of protein-protein interactions and intramolecular contacts to the mode of action of this class of compounds. These discoveries have opened the door to a new paradigm for structure-guided drug design: borrowing surface area and molecular recognition from nature to elicit cellular signalling.

Keywords: PROTACs; molecular glues; protein degradation; protein-protein interactions; ternary complexes.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1
Figure 1. Comparison of binary and ternary therapeutic approaches
Figure 2
Figure 2. Molecular glues
(A) Crystal structure of DDB1:CRBN:CC-885:GSPT1 (PDB ID: 5HXB) [36] and (B) crystal structure of DDB1:CRBN:lenalidomide:CK1α (PDB ID: 5FQD) [37]. (C) Chemical structures of several IMiDs. (D) Schematic illustrating the modification of binding surfaces by molecular glues.
Figure 3
Figure 3. Proteolysis-targeting chimaeras
(A) PROTACs hijack E3 ligases to trigger the ubiquitination and subsequent proteasomal degradation of a target protein. Ub - ubiquitin. (B) Chemical structures of PROTACs that recruit BET proteins and either VHL (MZ1) or CRBN (dBET1 and ARV-825).
Figure 4
Figure 4. Existing mindset in PROTAC design and optimization
The prevailing approach to developing new PROTACs views ligands targeting the E3 Ligase (blue) and the Target Protein (green) as separate entities that can be joined by a linker.
Figure 5
Figure 5. PROTAC-induced ternary complexes and their biophysical properties
(A) Crystal structure of VHL:MZ1:Brd4BD2 (PDB ID: 5T35). (B) Conformation of MZ1 when bound to the ternary complex. (C) Ternary (T) complex equilibria for protein A, protein B and PROTAC (P). (D) Simulation showing amount of ternary complex formation and its relationship with cooperativity. KdA and KdB are maintained constant for all three cases.
Figure 6
Figure 6. The process of PROTAC development
The chart highlights the various steps involved from administration to intracellular degradation and the biophysical techniques used to study them. In bold are common parameters to characterize PROTACs at each stage.
See this image and copyright information in PMC

References

    1. Perutz M.F., Rossmann M.G., Cullis A.F., Muirhead H., Will G. and North A.C. (1960) Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-A. resolution, obtained by X-ray analysis. Nature 185, 416–422 - PubMed
    1. Beddell C.R., Goodford P.J., Norrington F.E., Wilkinson S. and Wootton R. (1976) Compounds designed to fit a site of known structure in human haemoglobin. Br. J. Pharmacol. 57, 201–209 - PMC - PubMed
    1. Rahuel J., Priestle J.P. and Grutter M.G. (1991) The crystal structures of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor. J. Struct. Biol. 107, 227–236 - PubMed
    1. Dhanaraj V., Dealwis C.G., Frazao C., Badasso M., Sibanda B.L., Tickle I.J. et al. (1992) X-ray analyses of peptide-inhibitor complexes define the structural basis of specificity for human and mouse renins. Nature 357, 466–472 - PubMed
    1. Navia M.A., Fitzgerald P.M., McKeever B.M., Leu C.T., Heimbach J.C., Herber W.K. et al. (1989) Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 337, 615–620 - PubMed

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