Macromolecular docking of a three-body system: The recognition of human growth hormone by its receptor

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.