The article reviews the structural basis of integrin regulation and signaling, focusing on the α I domain and the global topology of integrins. Integrins are cell adhesion molecules that mediate various cellular processes, including leukocyte trafficking, migration, and immune synapse formation. The adhesiveness of integrins can be dynamically regulated through inside-out signaling, where intracellular signals alter their affinity for extracellular ligands, and outside-in signaling, where ligand binding transduces signals from the extracellular to the cytoplasmic domain. The α I domain, a key component of integrins, is responsible for ligand binding and conformational regulation. Structural studies have revealed that the α I domain adopts a dinucleotide-binding fold and can exist in three distinct conformations: closed, intermediate, and open. The closed conformation is the low-energy state, while the open conformation is associated with higher-affinity states. Conformational changes in the α I domain are coupled to movements in other integrin domains, particularly the β6-α7 loop and the C-terminal α7-helix, which are crucial for ligand binding and signaling. The global topology of integrins involves the N-terminal ligand-binding head domain, the β-propeller domain, and the C-terminal legs. The β I domain, homologous to the α I domain, plays a role in ligand binding and allostery. The interaction between the α I and β I domains is essential for conformational regulation, with an invariant Glu residue in the αL linker required for α I domain activation. Integrin extension, induced by physiological stimuli, is a critical step in activating integrin adhesiveness. This extension involves a large-scale rearrangement of the ectodomain, leading to the swing-out of the hybrid domain and increased affinity for ligands. The compliant nature of the β legs facilitates this extension, which optimizes the orientation of the ligand-binding site for adhesion. The article also discusses the role of integrin lateral association and clustering, which is thought to be important for priming and efficient ligand binding. However, the exact mechanisms and regulation of this process remain controversial. Overall, the review provides a comprehensive overview of the structural and functional aspects of integrin regulation, highlighting the importance of conformational changes in mediating integrin signaling and adhesion.The article reviews the structural basis of integrin regulation and signaling, focusing on the α I domain and the global topology of integrins. Integrins are cell adhesion molecules that mediate various cellular processes, including leukocyte trafficking, migration, and immune synapse formation. The adhesiveness of integrins can be dynamically regulated through inside-out signaling, where intracellular signals alter their affinity for extracellular ligands, and outside-in signaling, where ligand binding transduces signals from the extracellular to the cytoplasmic domain. The α I domain, a key component of integrins, is responsible for ligand binding and conformational regulation. Structural studies have revealed that the α I domain adopts a dinucleotide-binding fold and can exist in three distinct conformations: closed, intermediate, and open. The closed conformation is the low-energy state, while the open conformation is associated with higher-affinity states. Conformational changes in the α I domain are coupled to movements in other integrin domains, particularly the β6-α7 loop and the C-terminal α7-helix, which are crucial for ligand binding and signaling. The global topology of integrins involves the N-terminal ligand-binding head domain, the β-propeller domain, and the C-terminal legs. The β I domain, homologous to the α I domain, plays a role in ligand binding and allostery. The interaction between the α I and β I domains is essential for conformational regulation, with an invariant Glu residue in the αL linker required for α I domain activation. Integrin extension, induced by physiological stimuli, is a critical step in activating integrin adhesiveness. This extension involves a large-scale rearrangement of the ectodomain, leading to the swing-out of the hybrid domain and increased affinity for ligands. The compliant nature of the β legs facilitates this extension, which optimizes the orientation of the ligand-binding site for adhesion. The article also discusses the role of integrin lateral association and clustering, which is thought to be important for priming and efficient ligand binding. However, the exact mechanisms and regulation of this process remain controversial. Overall, the review provides a comprehensive overview of the structural and functional aspects of integrin regulation, highlighting the importance of conformational changes in mediating integrin signaling and adhesion.