Crystal structure of human bone morphogenetic protein-2 at 2.7 angstrom resolution

Homodimeric bone morphogenetic protein-2 (BMP-2) is a member of the transfo rming growth factor beta (TGF-beta) superfamily that induces bone formation and regeneration, and determines important steps during early stages of em bryonic development in vertebrates and non-vertebrates. BMP-2 can interact with two types of receptor chains, as well as with proteins of the extracel lular matrix and several regulatory proteins. We report here the crystal st ructure of human BMP-2 determined by molecular replacement and refined to a n R-value of 24.2% at 2.7 Angstrom resolution. A common scaffold of BMP-2, BMP-7 and the TGP-beta s, i.e. the cystine-knot motif and two finger-like d ouble-stranded beta-sheets, can be superimposed with r.m.s. deviations of a round 1 Angstrom. In contrast to the TGF-beta s, the structure of BMP-2 sho ws differences in the flexibility of the N terminus and the orientation of the central a-helix as well as two external loops at the fingertips with re spect to the scaffold. This is also known from the BMP-7 model. Small secon dary structure elements in the loop regions of BMP-2 and BMP-7 seem to be s pecific for the respective BMP-subgroup. Two identical helix-finger clefts and two distinct cavities located around the central 2-fold axis of the dim er show characteristic shapes, polarity and surface charges. The possible f unction of these specific features in the interaction of BMP-2 with its bin ding partners is discussed. (C) 1999 Academic Press.