Latest progress within the improvement of affinity grids for cryoelectron microscopy (cryo-EM) sometimes employs genetic engineering of the protein pattern akin to histidine or Spy tagging, immobilized antibody seize, or nonselective immobilization by way of electrostatic interactions or Schiff base formation. We report a robust and versatile technique for the affinity seize of goal proteins for cryo-EM evaluation that makes use of small-molecule ligands as bait for concentrating human goal proteins immediately onto the grid floor for single-particle reconstruction. This method is demonstrated for human p97, captured utilizing two totally different small-molecule high-affinity ligands of this AAA+ ATPase. 4 electron density maps are revealed, every representing a p97 conformational state captured from resolution, together with a double-hexamer construction resolved to three.6 Å. These outcomes reveal that the noncovalent seize of protein targets on EM grids modified with high-affinity ligands can allow the construction elucidation of a number of configurational states of the goal and doubtlessly inform structure-based drug design campaigns.