Linker activation

Fig. 12 Zero-length cross-linker activation of native surface functionalities...

Scheme 7 Safety-catch linker activation by cobalt carbonyl complexation...

Since the discovery of SQ 83,360, compounds such as U-78,608 [123444-35-9] (64) having different linker groups between the hydroxypytidone group and the sulfonyl residue have been reported. U-78,608 and SQ 83,360 have similar in vitro and in vivo activity (45). 

Polyfunctional 2-hydtoxyalk5iamides can serve as cross-linkers for carboxyHc acid-terrninated polyester or acryHc resins (65). The hydroxyl group is activated by the neighboring amide linkage (66). SoHd grades of hydroxyamides are finding use as cross-linkers for powder coatings (67). 

Figure 13.30 Ribbon diagram of the structure of Src tyrosine kinase. The structure is divided in three units starting from the N-terminus an SH3 domain (green), an SH2 domain (blue), and a tyrosine kinase (orange) that is divided into two domains and has the same fold as the cyclin dependent kinase described in Chapter 6 (see Figure 6.16a). The linker region (red) between SH2 and the kinase is bound to SH3 in a polyproline helical conformation. A tyrosine residue in the carboxy tail of the kinase is phosphorylated and bound to SH2 in its phosphotyrosine-binding site. A disordered part of the activation segment in the kinase is dashed. (Adapted from W. Xu et al.. Nature 385 595-602, 1997.)...

Figure 13.32 Regulation of the catalytic activity of members of the Src family of tyrosine kinases, (a) The inactive form based on structure determinations. Helix aC is in a position and orientation where the catalytically important Glu residue is facing away from the active site. The activation segment has a conformation that through steric contacts blocks the catalytically competent positioning of helix aC. (b) A hypothetical active conformation based on comparisons with the active forms of other similar protein kinases. The linker region is released from SH3, and the activation segment changes its structure to allow helix aC to move and bring the Glu residue into the active site in contact with an important Lys residue.

Src tyrosine kinase contains both an SH2 and an SH3 domain linked to a tyrosine kinase unit with a structure similar to other protein kinases. The phosphorylated form of the kinase is inactivated by binding of a phosphoty-rosine in the C-terminal tail to its own SH2 domain. In addition the linker region between the SH2 domain and the kinase is bound in a polyproline II conformation to the SH3 domain. These interactions lock regions of the active site into a nonproductive conformation. Dephosphorylation or mutation of the C-terminal tyrosine abolishes this autoinactivation. 

Endonuclease-catalyzed hydrolysis of DNA at the internucleosomal linker regions into multimers of 180 base pairs which are visualized by electrophoresis as a ladder of nuclear DNA fragments. Access of the endonuclease to DNA is facilitated by depletion of polyamines, and the activity of the enzyme is mcrea.sed by and decreased by ADP-tibosylation. Thus, agents that increase intracellular Ca " or inhibit l>oly(ADP-ribose) polymerase can induce apoptosi.s. ... 

Structure-activity studies of 5,6,7,8-tetrahdyro-5,5,8,8-tetramethyl-2-quinoxaline derivatives necessitated the preparation of thiophene-containing compound 17. Stetter conditions using thiazolium salt 20 as catalyst resulted in the preparation of 1,4-diketone 21 from 18 and 19. Condensation of 21 with phosphorus pentasulfide followed by saponification resulted in 17. In this fashion, the authors replaced the amide linker of parent compound 22 with the rigid thiophene moiety. 

In a different approach, a TNF fusion protein designated TNF-Selectokine has been described [5]. This TNF prodrug is comprised of a trimeric scFv-TNF fusion protein to which a TNFR fragment has been fused at the C-terminal. A flexible peptide linker between TNF and the blocking receptor domain is comprised of sequences specifically recognized by tumor associated proteases such as tissue plasminogen activator, urokinase type plasminogen activator or... 

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