Article

Nature 420, 636-642 (12 December 2002) | doi:10.1038/nature01245; Received 21 May 2002; Accepted 15 October 2002

Structural basis of BMP signalling inhibition by the cystine knot protein Noggin

Jay Groppe1,2, Jason Greenwald1, Ezra Wiater3, Joaquin Rodriguez-Leon4, Aris N. Economides5, Witek Kwiatkowski1, Markus Affolter2, Wylie W. Vale3, Juan Carlos Izpisua Belmonte4,6 & Senyon Choe1

  1. Structural Biology, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
  2. Peptide Biology, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
  3. Gene Expression Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
  4. Instituto Gulbenkian de Ciencia, Rua da Quinta Grande, Oeiras 2780-901, Portugal
  5. Biozentrum, Klingelbergstrasse 50-70, Basel CH-4056, Switzerland
  6. Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, New York, New York 10591, USA

Correspondence to: Senyon Choe1 Correspondence and requests for materials should be addressed to S.C. (e-mail: Email: choe@salk.edu). Coordinates for the structure have been deposited in the Protein Data Bank (accession code 1M4U).

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The interplay between bone morphogenetic proteins (BMPs) and their antagonists governs developmental and cellular processes as diverse as establishment of the embryonic dorsal–ventral axis, induction of neural tissue, formation of joints in the skeletal system and neurogenesis in the adult brain. So far, the three-dimensional structures of BMP antagonists and the structural basis for inactivation have remained unknown. Here we report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. The BMP-7-binding affinity of site-specific variants of Noggin is correlated with alterations in bone formation and apoptosis in chick limb development, showing that Noggin functions by sequestering its ligand in an inactive complex. The scaffold of Noggin contains a cystine (the oxidized form of cysteine) knot topology similar to that of BMPs; thus, ligand and antagonist seem to have evolved from a common ancestral gene.