Venomous snakes have evolved an intricate biochemical arsenal composed of diverse, pharmacologically active proteins and peptides, underpinning their effectiveness in predation and defence. While advances in genomics and proteomics have rapidly expanded our knowledge of venom components at the primary sequence level, current approaches often overlook the structural and functional complexity arising from proteoforms, post-translational modifications, and higher-order protein interactions, factors that critically influence venom potency and therapeutic potential.
This presentation highlights our recent progress in developing advanced mass spectrometry (MS)-based workflows for structural venomics. Leveraging top-down and native MS in combination with ion mobility spectrometry (IM-MS), we have established a complex-centric proteomic profiling platform capable of resolving intact proteins and their interactomes with high specificity and throughput. Application of this platform to venoms from medically significant snake species has revealed striking structural diversity, including subtle proteoform variations and oligomeric assemblies that modulate bioactivity.
Through integrated structural and functional analyses, including bioactivity assays, we demonstrate that the toxic potential of venoms is not solely dictated by protein identity or abundance, but also by the structural context in which these proteins exist. Our findings underscore the necessity of incorporating higher-order structural insights into venom research to fully understand envenomation mechanisms, improve antivenom strategies, and unlock new avenues for biotechnological innovation.