Structure of Human Growth Hormone

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Although little sequence identity exists among members of the hematopoietic cytokine family, most have either been shown or predicted to be four-helical bundles (3). The four-helix bundle structural motif was first described with the crystal structure for the porcine growth hormone (6). In the case of hGH, the four-helical bundle topology was first observed in the crystal structure of the hGH-hGHR complex (7). Hormones belonging to this group can be subdivided into two general classes called short-chain and long-chain. hGH is classified as a long-chain helical cytokine because of the length of each of the helices (between 21 and 30 amino acids). All members of this cytokine group are characterized by an antiparallel up-up-down-down arrangement of the helices. This helical organization requires rather long extended loops between helices 1 and 2 and helices 3 and 4 (Fig. 1). In hGH, helices 1 and 4 are longer (26 and 30 residues) than helices 2 and 3 (21 and 23 residues).

Overall, the four-helical bundle topology of hGH makes for a very compact and stable molecule. Most of the inner core of the four-helix bundle consists of hydrophobic residues. hGH contains two disulfide bonds. One disulfide connects the first crossover loop to helix 4 via a C53 to C165 linkage. The other disulfide bridge (C182 to C189) connects the C-terminus to the end of helix 4. Additionally, hGH contains three prominent, yet short, minihelical segments. Two of these minihelical segments, between residues 38-47 and 64-70 in the connecting segment between helix 1 and 2, play significant roles in receptor binding. In uncomplexed hGH, significant portions of helices 1, 3, and 4 are exposed to solvent (7,8). Most of the residues on helix 2 are either buried in the core or are covered by the helix 3 to helix 4 connecting loop. The importance of each of the solvent exposed helical surfaces in binding the hGHR will become evident with further discussion.

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