Dk. Hendrix et al., Macromolecular docking of a three-body system: The recognition of human growth hormone by its receptor, PROTEIN SCI, 8(5), 1999, pp. 1010-1022
Human growth hormone (hGH) binds to its receptor (hGHr) in a three-body int
eraction: one molecule of the hormone and two identical monomers of the rec
eptor form a trimer. Curiously, the hormone-receptor interactions in the tr
imer are not equivalent and the formation of the complex occurs in a specif
ic kinetic order (Cunningham BC, Ultsch M, De Vos AM, Mulkerrin MG, Clauser
KR, Wells JA, 1991, Science 254:821-825). In this paper, we model the reco
gnition of hGH to the hGHr using shape complementarity of the three-dimensi
onal structures and macromolecular docking to explore possible binding mode
s between the receptor and hormone. The method, reported previously (Hendri
x DK, Kuntz ID, 1998, Pacific symposium on biocomputing 1998, pp 1234-1244)
, is based upon matching complementary-shaped strategic sites on the molecu
lar surface. We modify the procedure to examine three-body systems. We find
that the order of binding seen experimentally is also essential to our mod
el. We explore the use of mutational data available for hGH to guide our mo
del. In addition to docking hGH to the hGHr, we further test our methodolog
y by successfully reproducing 16 macromolecular complexes from X-ray crysta
l structures, including enzyme-inhibitor, antibody-antigen, protein dimer,
and protein-DNA complexes.