Multiple molecular dynamics simulations of human LOX-1 and Trp150Ala mutant reveal the structural determinants causing the full deactivation of the receptor

Abstract

Multiple classical molecular dynamics simulations have been applied to the human LOX-1 receptor to clarify the role of the Trp150Ala mutation in the loss of binding activity. Results indicate that the substitution of this crucial residue, located at the dimer interface, markedly disrupts the wild-type receptor dynamics. The mutation causes an irreversible rearrangement of the subunits interaction pattern that in the wild-type protein allows the maintaining of a specific symmetrical motion of the monomers. The subunits dislocation determines a loss of linearity of the arginines residues composing the basic spine and a consequent alteration of the long-range electrostatic attraction of the substrate. Moreover, the anomalous subunits arrangement observed in the mutated receptor also affects the integrity of the hydrophobic tunnel, actively involved in the short-range hydrophobic recognition of the substrate. The combined effect of these structural rearrangements generates the impairing of the receptor function.

Secondary Sites of the C‐type Lectin‐Like Fold

“…[15,18,[83][84][85][86] In LOX-1, hinge dynamics around the dimer axis, observed in molecular dynamics simulations and X-ray crystallographic structures, have been suggested to impact the binding of oxLDL. [87][88][89] For DC-SIGN, previous reports indicated contraction of the tetrameric extracellular domain by 5 nm upon Man 9 GlcNAc 2 binding, resulting from flexibility of the linkage between CRD and stalk domain. [90,91] Moreover, DC-SIGN targeted antibodies induced distinct endocytic mechanisms depending on their epitope at the DC-SIGN extracellular domain, suggesting translation of extracellular ligand binding across the plasma membrane.…”

“…Binding of the sialyl Lewis X oligosaccharide to E‐selectin induces conformational change in the long loop region, translating into a hinge‐bending motion of the CTLD relative to the EGF and the CR domains from a low affinity bent conformation to a high affinity extended conformation, providing detailed insights into the force‐enhanced mechanisms underlying cellular adhesion in the context of leukocyte trafficking [15,18,83–86] . In LOX‐1, hinge dynamics around the dimer axis, observed in molecular dynamics simulations and X‐ray crystallographic structures, have been suggested to impact the binding of oxLDL [87–89] . For DC‐SIGN, previous reports indicated contraction of the tetrameric extracellular domain by 5 nm upon Man 9 GlcNAc 2 binding, resulting from flexibility of the linkage between CRD and stalk domain [90,91] .…”

“…Second, a basic spine formed by arginine residues diagonally crossing the dimer surface has been identified as the binding site for amphipathic α‐helices on the surface of oxLDL particles (Figure 3a and b). [41,87,88,117–119] …”

“…[40,[114][115][116] Second, a basic spine formed by arginine residues diagonally crossing the dimer surface has been identified as the binding site for amphipathic α-helices on the surface of oxLDL particles (Figure 3a and b). [41,87,88,[117][118][119] Alongside their diverging ligand preferences, secondary sites have been frequently associated with increased selectivity and druggability compared to their canonical counterparts. [97,120,121] Different approaches revealed secondary binding sites for drug-like small molecules in several CLRswith important implications for novel modes of modulating their function.…”