A Three-State Mechanism of Integrin Activation and Signal Transduction for Integrin αvβ3

Abstract

Calcium ion shifts appear to be important for integrin conformational changes in binding processes. Ligand binding and signal transduction of integrins are poorly understood. Here we present a three‐state model of a signal transduction event (see figure) based on molecular modeling and docking studies of integrin αvβ3 that involves allosteric effects triggered by a ligand‐induced shift of a Ca2+ ion.

Binding Model for Nonpeptide Antagonists of αvβ3 Integrin

“…In addition, a recent communication by Gottschalk et al identified the general binding region of the basic terminus of their ligand as D148 and Y178. 35 Taken together, the proposed model is consistent not only with observed activity as well as mutagenicity and photoaffinity cross-linking studies of the R v β 3 integrin but with these recently published results.…”

Binding Model for Nonpeptide Antagonists of αvβ3 Integrin

“…In addition, a recent communication by Gottschalk et al identified the general binding region of the basic terminus of their ligand as D148 and Y178. 35 Taken together, the proposed model is consistent not only with observed activity as well as mutagenicity and photoaffinity cross-linking studies of the R v β 3 integrin but with these recently published results.…”

Chemical Adaptor Immunotherapy: Design, Synthesis, and Evaluation of Novel Integrin-Targeting Devices

“…Initially, we performed the docking calculations with structure 76 to reproduce the observed binding mode of the cyclic RGD peptide in the crystal structure of the integrin−ligand complex . We also calculated the molecular docking of compound 72 and compared the results with the published data by Kessler et al25b Molecular docking of both 72 and 76 was in close agreement with the reported data (see Supporting Information). Next, we calculated the molecular docking of compounds 73 and 74 , the results of which are shown in Figures and , respectively.…”

Discovery of Small Molecule Integrin αvβ3 Antagonists as Novel Anticancer Agents

“…Several discrepancies were found in the previously predicted binding orientations of RGD mimetic peptidomimetic and non-peptide small-molecule antagonists. [43][44][45][46][47] Previously reported docking studies using nonpeptide small-molecule antagonists also predicted very similar binding orientations to the orientation predicted in this study. 43,45 However, docking studies performed on cyclic-RGD analogues and RGD mimetics produced binding orientations similar to the bound conformation of the cyclic RGD in the R v β 3 -RGD complex crystal structure.…”

“…[43][44][45][46][47] Previously reported docking studies using nonpeptide small-molecule antagonists also predicted very similar binding orientations to the orientation predicted in this study. 43,45 However, docking studies performed on cyclic-RGD analogues and RGD mimetics produced binding orientations similar to the bound conformation of the cyclic RGD in the R v β 3 -RGD complex crystal structure. 46,47 The observed discrepancies between the predicted binding orientations of our novel antagonists and bound conformation of the cyclic RGD peptide in the R v β 3 -RGD complex crystal structure may be due to a significant structural difference between the cyclic RGD peptide and these novel antagonists.…”

Binding Model for Nonpeptide Antagonists of αvβ3 Integrin

“…In addition, a recent communication by Gottschalk et al identified the general binding region of the basic terminus of their ligand as D148 and Y178. 35 Taken together, the proposed model is consistent not only with observed activity as well as mutagenicity and photoaffinity cross-linking studies of the R v β 3 integrin but with these recently published results.…”

Chemical Adaptor Immunotherapy: Design, Synthesis, and Evaluation of Novel Integrin-Targeting Devices

“…Initially, we performed the docking calculations with structure 76 to reproduce the observed binding mode of the cyclic RGD peptide in the crystal structure of the integrin−ligand complex . We also calculated the molecular docking of compound 72 and compared the results with the published data by Kessler et al25b Molecular docking of both 72 and 76 was in close agreement with the reported data (see Supporting Information). Next, we calculated the molecular docking of compounds 73 and 74 , the results of which are shown in Figures and , respectively.…”

Discovery of Small Molecule Integrin αvβ3 Antagonists as Novel Anticancer Agents

“…Several discrepancies were found in the previously predicted binding orientations of RGD mimetic peptidomimetic and non-peptide small-molecule antagonists. [43][44][45][46][47] Previously reported docking studies using nonpeptide small-molecule antagonists also predicted very similar binding orientations to the orientation predicted in this study. 43,45 However, docking studies performed on cyclic-RGD analogues and RGD mimetics produced binding orientations similar to the bound conformation of the cyclic RGD in the R v β 3 -RGD complex crystal structure.…”

“…[43][44][45][46][47] Previously reported docking studies using nonpeptide small-molecule antagonists also predicted very similar binding orientations to the orientation predicted in this study. 43,45 However, docking studies performed on cyclic-RGD analogues and RGD mimetics produced binding orientations similar to the bound conformation of the cyclic RGD in the R v β 3 -RGD complex crystal structure. 46,47 The observed discrepancies between the predicted binding orientations of our novel antagonists and bound conformation of the cyclic RGD peptide in the R v β 3 -RGD complex crystal structure may be due to a significant structural difference between the cyclic RGD peptide and these novel antagonists.…”

Binding Model for Nonpeptide Antagonists of αvβ3 Integrin

“…In addition, a recent communication by Gottschalk et al identified the general binding region of the basic terminus of their ligand as D148 and Y178. 35 Taken together, the proposed model is consistent not only with observed activity as well as mutagenicity and photoaffinity cross-linking studies of the R v β 3 integrin but with these recently published results.…”

Chemical Adaptor Immunotherapy: Design, Synthesis, and Evaluation of Novel Integrin-Targeting Devices

“…Initially, we performed the docking calculations with structure 76 to reproduce the observed binding mode of the cyclic RGD peptide in the crystal structure of the integrin−ligand complex . We also calculated the molecular docking of compound 72 and compared the results with the published data by Kessler et al25b Molecular docking of both 72 and 76 was in close agreement with the reported data (see Supporting Information). Next, we calculated the molecular docking of compounds 73 and 74 , the results of which are shown in Figures and , respectively.…”

Discovery of Small Molecule Integrin αvβ3 Antagonists as Novel Anticancer Agents

“…Several discrepancies were found in the previously predicted binding orientations of RGD mimetic peptidomimetic and non-peptide small-molecule antagonists. [43][44][45][46][47] Previously reported docking studies using nonpeptide small-molecule antagonists also predicted very similar binding orientations to the orientation predicted in this study. 43,45 However, docking studies performed on cyclic-RGD analogues and RGD mimetics produced binding orientations similar to the bound conformation of the cyclic RGD in the R v β 3 -RGD complex crystal structure.…”

“…[43][44][45][46][47] Previously reported docking studies using nonpeptide small-molecule antagonists also predicted very similar binding orientations to the orientation predicted in this study. 43,45 However, docking studies performed on cyclic-RGD analogues and RGD mimetics produced binding orientations similar to the bound conformation of the cyclic RGD in the R v β 3 -RGD complex crystal structure. 46,47 The observed discrepancies between the predicted binding orientations of our novel antagonists and bound conformation of the cyclic RGD peptide in the R v β 3 -RGD complex crystal structure may be due to a significant structural difference between the cyclic RGD peptide and these novel antagonists.…”