Regulatory domains

Compared to active-site-binders, allosteric inhibitors have the advantage of being active against resistant enzymes with active-site mutations and may have increased specificity for a given sub-family of enzymes. To search for allosteric drug-target sites, we study the structural basis of enzyme activation in specific cellular processes. Our strategy is focused towards identifying conformations of the enzyme ― present either stably or transiently during activation ― that are specific to a given biological pathway. These conformations can be targeted to develop pathway-specific inhibitors.

Figure 1: SHP2 bound to ITIM–ITSM bidentate peptide
Figure 1. Superposition of the structures of SHP2 (residues 1–220; comprising the N-SH2 (blue) and C-SH2 (green) domains) from PDBs 2SHP (closed or auto-inhibited state of SHP2; solved without bound peptide) and 3PS5 (open state of SHP1; solved with bound peptide). The peptide shown here in pink is the doubly phosphorylated ITIM–ITSM peptide from the cytoplasmic tail of PD-1. The two structures are aligned on the C-SH2 domain (green). The figure shows how the N-SH2 domain changes its position with respect to the C-SH2 domain, transitioning from the closed, auto-inhibited conformation to the open conformation upon binding the tail of PD-1.

As an example of these efforts, we have studied the PD-1-dependent activation of SHP2 during the process of cancer immune escape. The cytoplasmic Src-homology02 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is involved in various kinds of leukaemia and solid tumours and is also a key mediator of inhibitory receptor signalling through its interaction with immune checkpoint receptors such as PD-1. The success of anti-cancer therapy based on monoclonal antibodies that disrupt PD-1 signaling suggests that blocking the SHP2–PD-1 interaction by targeting SHP2 may result in an efficient and inexpensive anti-cancer strategy. This hypothesis is supported by many reports demonstrating the role of SHP2 in T-cell activation.

Using a combination of structural and computational methods, we have established the structural details of the PD-1-mediated SHP2 activation and identified three routes to modulating SHP2 activation (Marasco et al., Science Advances, 2020; Figure 1). Currently, we are focusing on one of the SHP2 structural models determined during this work to develop small molecules that are capable of down-regulating PD-1-dependent SHP2 activation.