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

Published online by Cambridge University Press:  01 May 1999

DONNA K. HENDRIX ,
TERI E. KLEIN  and
IRWIN D. KUNTZ
DONNA K. HENDRIX
Affiliation:
Department of Pharmaceutical Chemistry, University of California, San Francisco, 513 Parnassus, San Francisco, California 94143–0446 Graduate Group in Biophysics, University of California, San Francisco, 513 Parnassus, San Francisco, California 94143–0448
TERI E. KLEIN
Affiliation:
Department of Pharmaceutical Chemistry, University of California, San Francisco, 513 Parnassus, San Francisco, California 94143–0446
IRWIN D. KUNTZ
Affiliation:
Department of Pharmaceutical Chemistry, University of California, San Francisco, 513 Parnassus, San Francisco, California 94143–0446
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Abstract

Human growth hormone (hGH) binds to its receptor (hGHr) in a three-body interaction: one molecule of the hormone and two identical monomers of the receptor form a trimer. Curiously, the hormone-receptor interactions in the trimer are not equivalent and the formation of the complex occurs in a specific 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 recognition of hGH to the hGHr using shape complementarity of the three-dimensional structures and macromolecular docking to explore possible binding modes between the receptor and hormone. The method, reported previously (Hendrix DK, Kuntz ID, 1998, Pacific symposium on biocomputing 1998, pp 1234–1244), is based upon matching complementary-shaped strategic sites on the molecular surface. We modify the procedure to examine three-body systems. We find that the order of binding seen experimentally is also essential to our model. We explore the use of mutational data available for hGH to guide our model. In addition to docking hGH to the hGHr, we further test our methodology by successfully reproducing 16 macromolecular complexes from X-ray crystal structures, including enzyme-inhibitor, antibody-antigen, protein dimer, and protein-DNA complexes.

Keywords

EPOerythropoietinfunctional epitopehuman growth hormonemacromolecular dockingmacromolecular interactionsmacromolecular recognitionstructural epitope
Type
Research Article
Information
Protein Science , Volume 8 , Issue 5 , May 1999 , pp. 1010 - 1022
Copyright
1999 The Protein Society

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