Reverse Dimerization ligand

This conceptually simple approach, described more than 10 years ago [3], has proved broadly applicable and has been widely adopted not only in the chemical biology community but also across biological research in general. It has also spawned several related technologies, such as systems for reverse dimerization . This chapter will review the various protein-ligand systems that have been designed, and describe examples of their use, both in research and drug discovery. 

A fortuitous discovery has led to the development of a reverse dimerization system, in which protein-protein association represents the ground state, and addition of ligand disrupts dimerization (Fig. 4.2-7). During the bumps-and-holes engineering of FKBP, it was discovered that the F36M mutant... 

Fig. 4.2-7 Comparison of conventional and proteins, (b) Reverse dimerization system "reverse FKBP dimerization systems. using monomeric ligand (AP21998) and (a) Induced dimerization using bumped F36M fusion proteins, homodimerizer AP20187 and F36V fusion...

Fig. 4.2-12 Use of the reverse dimerization system to control protein secretion in mammalian cells, (a) Scheme for inducible secretion, (b) Chemical structure of monomeric ligand AP21998. (c) Pulsatile release of insulin from engineered cells. 

M. Gilman, T. Clackson, A ligand-reversible dimerization system for controlling protein-protein interactions, Proc. Natl. Acad. Sci. 

Carl T. Rollins, Victor M. Rivera, Derek N. Woolfson, Terence Keenan, Marcos Hatada, Susan E. Adams, Lawrence J. Andrade, David Yaeger, Marie Rose van Schravendijk, Dennis A. Holt, Michael Gilman and Tim Clackson, A ligand-reversible dimerization system for controlling protein-protein interactions. Proceedings of the National Academy of Sciences USA, 97 (2000), 7096-7101. 

The molybdenum and tunsten diphenylacetylene compounds have been chemically useful primarily as precursors to the quadruple metal-metal bonded dimers [M(Por)]2, formed by solid-state vacuum pyrolysis reactions. However. Mo(TTP)()/"-PhC CPh) is also a useful substrate in atom-transfer reactions, reacting with Sx or Cp2TiS i to form Mo(TTP)=S. The reaction can be reversed by treatment of Mo(TTP)=S with PPh (which removes sulfur as PhxP=S) and PhC CPh. The order of preference for ligand binding to molybdenum 11) has been established to be PPh < PhC CPh < 4-picoline. ... 

The characterization and crystal structure of the dimer [Pt2( -dppm)3] (dppm = bis(diphenyl-phosphino)methane), first reported as a deep red complex in 1978, was described by Manojlovic-Muir et al. in 1986.11 The structure, the first of its type, is made up of two parallel and almost eclipsed trigonal-planar platinum moieties bridged by three diphosphine ligands. The Pf Pt separation is 3.0225(3) A, too long to be considered a bond.11 [Pt2(//-dppm)3] catalyzes the hydrogenation/reduction of carbon dioxide with dimethylamine to give dimethylformamide12 (Equation (1)) and the reverse reaction.13... 

The A-frame hydride [Pt2H2(/i-H)(/i-dppm)2] undergoes reductive elimination of H2 in the presence of tertiary phosphine ligands, L, to give the platinum(I) dimer, [Pt2HL(//-dppm)2]. Hill and Puddephatt have shown that this occurs via the intermediate [Pt2II2(/i-H)L(//-dppm)2] (14).99 Carbon monoxide reacts rapidly and reversibly with [PtH(/r-PP)2Pt(CO)]+, PP = R2P-CH2-PR2, R = Et or Ph, to give [PtH(/i-PP)2Pt(CO)2]+ and [PtH(CO)(/u-PP)2Pt(CO)2]+, the first reported mixed valence, platinum(0)-platinum(ll) complexes.100... 

Such reactions are initiated by a single electron transfer from the dialkylzinc moiety to the diazabutadiene ligand to afford radical pairs 109, which collapse by the regioselective transfer of the organic radical to the nitrogen 110 or carbon 111 atoms of the diazabutadiene moiety. If the alkyl radical escapes from the organozinc radical, the latter dimerizes reversibly to 112 via the formation of a very long yet credible carbon-carbon bond. 

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