FIGURE 8.

Proposed structural effects of hADAMDEC1 mutations and basis of substrate/inhibitor interactions. A, superposition of the modeled Zn²⁺-binding active sites of hWT (gray), hD362H (green), and hC392S (cyan). Catalytic water molecules are marked by a light red cross. The identified disulfide bond connecting Cys³⁶⁹ and Cys³⁷⁴ is visible on the right. B and C, proposed docking of a peptide substrate (dark gray sticks) in an electrostatic surface model of hADAMDEC1. The substrate, AFKCm↓LKDG, represents the dominant hADAMDEC1-mediated cleavage of Cm-Tf. D, docking of N-TIMP-3 into the structural model of ADAMDEC1 based on the crystal structure of N-TIMP-3 in complex with ADAM-17 (PDB entry 3CKI (27)). N-TIMP-3 interacts directly with the catalytic Zn²⁺ through the backbone amino and carbonyl groups of Cys¹ and with the substrate binding pockets through multiple amino acid side chains (as indicated in the figure). E, the interaction of N-TIMP-3 Glu⁶⁵ with the backbone of Asp³⁶² in hWT (gray) and His³⁶² of the hD362H variant (green).