Integrins are composed of noncovalently bound dimers of an α‐ and a β‐subunit. They play an important role in cell‐matrix adhesion and signal transduction through the cell membrane. Signal transduction can be initiated by the binding of intracellular proteins to the integrin. Binding leads to a major conformational change. The change is passed on to the extracellular domain through the membrane. The affinity of the extracellular domain to certain ligands increases; thus at least two states exist, a low‐affinity and a high‐affinity state. The conformations and conformational changes of the transmembrane (TM) domain are the focus of our interest. We show by a global search of helix–helix interactions that the TM section of the family of integrins are capable of adopting a structure similar to the structure of the homodimeric TM protein Glycophorin A. For the α_IIbβ₃ integrin, this structural motif represents the high‐affinity state. A second conformation of the TM domain of α_IIbβ₃ is identified as the low‐affinity state by known mutational and nuclear magnetic resonance (NMR) studies. A transition between these two states was determined by molecular dynamics (MD) calculations. On the basis of these calculations, we propose a three‐state mechanism.