Each IGF1 receptor is made of two half-receptors, which are linked by disulfide bonds (not shown). The six domains in the extracellular region of the first half-receptor (orange) are L1, CR, L2, Fn1, Fn2 and Fn3; the domains in the second half-receptor (green) are the same and labeled with an asterisk. The domains outlined in black are in the so-called α chain, and the domains outlined in blue are in the β chain of each half-receptor; the Fn2 domain consists of both chains. The intracellular region comprises the juxtamembrane region (JM) and the tyrosine kinase domain (KIN). Sites of trans-phosphorylation are shown as circles. (A) When IGF1 is not bound to the receptor, an interaction between L1* of the second half-receptor and Fn2 and Fn3 of the first half-receptor (and vice versa) is thought to maintain a large separation between the transmembrane (TM) helices (dotted arrow). (B) When IGF1 binds to L1* (or to L1), it disrupts the L1*-Fn2 (or L1-Fn2*) interaction. This allows Fn2 and Fn3 of each half-receptor to pivot (grey arrows) towards each other (the previous positions of Fn2 and Fn3 are shown semi-transparently). This in turn facilitates the dimerization of the TM helices in the membrane, which juxtaposes the kinase domains for efficient trans-phosphorylation (black arrows). Binding of a single IGF1 molecule (shown as binding to the left side) is sufficient to activate the receptor, but exactly how this asymmetry affects the conformational changes in the receptor is unclear.