(512d) Role of a Tandem Hormone-Binding Element in Insulin Recognition By the Insulin Receptor

Insulin regulates blood glucose levels in higher organisms by binding
to and activating insulin receptor (IR), a constitutively homodimeric
glycoprotein of the receptor tyrosine kinase (RTK) superfamily.
Therapeutic efforts in treating diabetes have been
significantly impeded by the absence of structural information on the
activated form of the insulin/IR complex. Many biophysical,
biochemical, and structural studies strongly suggest the possibility
of plasticity in hormone and the receptor structure. Specifically,
insulin is proposed undergo a conformational change in the C-terminus
of its B-chain, while receptor flexibility may in part be due to
rearrangement of the so-called CT-peptide, a tandem hormone-binding
element of IR. Using various atomistic simulation approaches, we have
constructed all-atom structural models of hormone/receptor complexes
in the presence of CT in its crystallographic position and a
thermodynamically favorable displaced position. The displacement of CT
is confirmed by recent structural studies on minimal receptor
constructs that can bind insulin. When aligned into a full ectodomain
structure of receptor, the new insulin-bound structures suffer many
severe steric clashes with these domains. Therefore, the likely
structural rearrangements in these domains on insulin binding yet
remain unclear. Starting with our displaced-CT structural model of
insulin/IR complex and by creating a simulated target density map from
the crystallographic data, we have generated a structural model of
insulin/IR complex without any structural overlap of hormone with
receptor domains. This refined structural model provides significant
insights into a new hormone/receptor contact surface other than
the classical insulin recognition surface on the receptor. The results
presented in this work have further implications for the design of
receptor-specific agonists/antagonists.