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Structural Basis of the Differential Binding of Engineered Knottins to Integrins ?V?3 and ?5?1.


ABSTRACT: Targeting both integrins ?V?3 and ?5?1 simultaneously appears to be more effective in cancer therapy than targeting each one alone. The structural requirements for bispecific binding of ligand to integrins have not been fully elucidated. RGD-containing knottin 2.5F binds selectively to ?V?3 and ?5?1, whereas knottin 2.5D is ?V?3 specific. To elucidate the structural basis of this selectivity, we determined the structures of 2.5F and 2.5D as apo proteins and in complex with ?V?3, and compared their interactions with integrins using molecular dynamics simulations. These studies show that 2.5D engages ?V?3 by an induced fit, but conformational selection of a flexible RGD loop accounts for high-affinity selective binding of 2.5F to both integrins. The contrasting binding of the highly flexible low-affinity linear RGD peptides to multiple integrins suggests that a "Goldilocks zone" of conformational flexibility of the RGD loop in 2.5F underlies its selective binding promiscuity to integrins.

SUBMITTER: Van Agthoven JF 

PROVIDER: S-EPMC6726563 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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