Assembly and inhibition of fibroblast growth factor signaling complexes
Two crystal structures of the ternary complex between FGF, FGFR and heparin (a functional and structural analogue of HS) have been determined, from which two models have been proposed; a symmetric model with 2:2:2 stoichiometry and an asymmetric model with 2:2:1 stoichiometry. It is not clear which...
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University of Cambridge
2010
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| Online Access: | http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596958 |
| Summary: | Two crystal structures of the ternary complex between FGF, FGFR and heparin (a functional and structural analogue of HS) have been determined, from which two models have been proposed; a symmetric model with 2:2:2 stoichiometry and an asymmetric model with 2:2:1 stoichiometry. It is not clear which architecture is observed in solution and how the complex forms. Here I dissect the kinetic and thermodynamic assembly of the FGF ternary complex by isothermal titration calorimetry (ITC). Results indicate that after secretion into the extracellular space, FGFs oligomerise on heparin in a process mediated by positive cooperativity. Co-crystal structures of FGF with heparin fragments of eight and sixteen saccharide moieties in length reveal that this cooperativity is mediated through a conformational change in the structure of heparin. Formation of a heterotrimer of FGF-heparin with a 2:1 stoichiometry then recruits two FGFR molecules into a ternary complex with a molecular mass consistent with the asymmetric model. Inhibition of FGF ternary complex formation and signalling is a key target for cancer drug development. Here I report a small-molecule allosteric modulator that binds the FGFR extracellular juxtamembrane domain and elicits a conformational change that has an inhibitory effect on FGF signalling in a signal pathway-biased manner. The antagonist has a low micromolar affinity and binds to a highly conserved allosteric site. <i>In silico</i> docking approaches demonstrate possible modes of interaction with the FGFR. Crystal structures of individual FGFR domains are presented and discussed with relevance to future drug discovery. |
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