Allosteric surface

The allosteric surface refers to regions on a protein's exterior, distinct from the active site, where allosteric modulators bind to regulate protein function through conformational changes that propagate to distant sites. These surfaces are often linked to protein sectors—networks of co-evolving residues that connect the active site to multiple surface hotspots, enabling signal transmission and functional modulation as seen in enzymes like dihydrofolate reductase (DHFR) and PDZ domains. Biologically, they facilitate processes such as enzyme catalysis, signaling, and cooperativity without directly participating in substrate binding. In disease contexts, targeting these surfaces is promising for "undruggable" proteins, offering higher specificity and lower toxicity than orthosteric drugs, with applications in cancer, inflammation, and infections where resistance to conventional therapies arises. Computational tools like STINGAllo identify these sites using residue nanoenvironments, including solvent accessibility, hydrophobicity, and electrostatics, distinguishing allosteric site-forming residues from others. Drug development leverages this for small molecules that bind surfaces to fine-tune activity, though challenges remain in accurate site prediction and nonlinear response mechanisms.

Other names

allosteric siteallosteric pocketsector-connected surface site

Binding of allosteric modulators to induce conformational changes that alter active site behavior or protein activity