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Structure of human follicle-stimulating hormone in complex with its receptor

Abstract

Follicle-stimulating hormone (FSH) is central to reproduction in mammals. It acts through a G-protein-coupled receptor on the surface of target cells to stimulate testicular and ovarian functions. We present here the 2.9-Å-resolution structure of a partially deglycosylated complex of human FSH bound to the extracellular hormone-binding domain of its receptor (FSHRHB). The hormone is bound in a hand-clasp fashion to an elongated, curved receptor. The buried interface of the complex is large (2,600 Å2) and has a high charge density. Our analysis suggests that all glycoprotein hormones bind to their receptors in this mode and that binding specificity is mediated by key interaction sites involving both the common α- and hormone-specific β-subunits. On binding, FSH undergoes a concerted conformational change that affects protruding loops implicated in receptor activation. The FSH–FSHRHB complexes form dimers in the crystal and at high concentrations in solution. Such dimers may participate in transmembrane signal transduction.

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Figure 1: Crystal structure of human FSH bound to FSHRHB.
Figure 2: Recognition of FSH by FSHRHB.
Figure 3: Interactions at the receptor–ligand interface.
Figure 4: Different conformations in free and receptor-bound FSH.
Figure 5: Dimer of the FSH–FSHRHB complex.

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Acknowledgements

We thank J. Lustbader and L. Lobel for discussion and access to the cDNA clones of human FSHR and FSH, which were originally provided by A. Hsueh and W. Moyle; N. Belgado and D. Hildesheim for help with insect cell culture work; T. Laue, R. Olson and E. Gouaux for advice on analytical ultracentrifugation experiments; M. A. Gawinowicz for sequencing and mass spectrometry; R. Henderson and R. Kovall for critical reading of the manuscript; L. Mosyak, J. Cheung, G. Gregorio, V. Grantcharova, D. Garboczi, C. Lusty and R. Jin for discussion; and synchrotron beamline staff for assistance with data collection. Beamline X4A at the National Synchrotron Light Source (NSLS) is supported by the New York Structural Biology Center, and beamline 31-ID at the Advanced Photon Source (APS) is supported by Structural GenomiX, Inc. NSLS and APS are Department of Energy facilities. Work was supported in part by an NIH grant. Q.R.F. is an Agouron Institute fellow of the Jane Coffin Childs Memorial Foundation.

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Correspondence to Wayne A. Hendrickson.

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This file contains Supplementary Figures S1-S5, Supplementary Table S1 and Supplementary Methods. It also contains additional references. (PDF 3262 kb)

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Fan, Q., Hendrickson, W. Structure of human follicle-stimulating hormone in complex with its receptor. Nature 433, 269–277 (2005). https://doi.org/10.1038/nature03206

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