TY - JOUR
T1 - Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization
AU - Schlessinger, Joseph
AU - Plotnikov, Alexander N.
AU - Ibrahimi, Omar A.
AU - Eliseenkova, Anna V.
AU - Yeh, Brian K.
AU - Yayon, Avner
AU - Linhardt, Robert J.
AU - Mohammadi, Moosa
N1 - Funding Information:
M. M. acknowledges S. R. Hubbard and X.-P. Kong for comments and helpful discussions and C. Ogata for synchrotron beamline assistance. Beamline X4A at the National Synchrotron Light Source, a DOE facility, is supported by the Howard Hughes Medical Institute. This work was supported in part by National Institutes of Health Grant R01 DE13686 (to M. M.). Correspondence and request for materials may be sent to [email protected].
PY - 2000
Y1 - 2000
N2 - The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 Å resolution has been determined. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led us to propose a revised model for FGFR dimerization. Biochemical data in support of this model are also presented. This model provides a structural basis for FGFR activation by small molecule heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.
AB - The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 Å resolution has been determined. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led us to propose a revised model for FGFR dimerization. Biochemical data in support of this model are also presented. This model provides a structural basis for FGFR activation by small molecule heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.
UR - http://www.scopus.com/inward/record.url?scp=0033635299&partnerID=8YFLogxK
U2 - 10.1016/S1097-2765(00)00073-3
DO - 10.1016/S1097-2765(00)00073-3
M3 - Article
C2 - 11030354
AN - SCOPUS:0033635299
SN - 1097-2765
VL - 6
SP - 743
EP - 750
JO - Molecular Cell
JF - Molecular Cell
IS - 3
ER -