Abstract

The objectives of this project are to establish the structural requirements for biological activity in the human glycoprotein hormones, luteinizing hormone (hLH) and human chorionic gonadotropin (hCG).
Under Aim 1, using previous NMR structure of LMB (38-57) as a baseline, Dr. Keutmann will continue NMR analysis to define structure. They then will use a monoclonal antibody as a """"""""surrogate receptor"""""""" in analysis of this ordered structure, in association with a binding site, using the technique of transferred nuclear-Overhauser effect spectroscopy.
Under Aim 2, to define more fully the surface topography.
Under Aim 2, to define more fully the surface topography of the receptor-associated peptide, they will determine the crystal structure of the loop in association with a Fab fragment of monoclonal antibody specific to the loop.
Under Aim 3, they will use site-directed mutagenesis to verify that biologically- significant modifications in the peptide are also significant in the whole hormone, and might also exert effects on structure elsewhere in the overlapping adjacent regions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD012851-14A1
Application #
2196939
Study Section
Endocrinology Study Section (END)
Project Start
1979-09-30
Project End
1997-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
14
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Keutmann, H T; Rubin, D A (1993) A subunit interaction site in human luteinizing hormone: identification by photoaffinity cross-linking. Endocrinology 132:1305-12
Keutmann, H T; Hua, Q X; Weiss, M A (1992) Structure of a receptor-binding fragment from human luteinizing hormone beta-subunit determined by [1H]- and [15N]nuclear magnetic resonance spectroscopy. Mol Endocrinol 6:904-13
Milius, R P; Keutmann, H T; Ryan, R J (1990) Molecular modeling of residues 38-57 of the beta-subunit of human lutropin. Mol Endocrinol 4:859-68
Keutmann, H T; Mason, K A; Kitzmann, K et al. (1989) Role of the beta 93-100 determinant loop sequence in receptor binding and biological activity of human luteinizing hormone and chorionic gonadotropin. Mol Endocrinol 3:526-31
Keutmann, H T; Charlesworth, M C; Kitzmann, K et al. (1988) Primary and secondary structural determinants in the receptor binding sequence beta-(38-57) from human luteinizing hormone. Biochemistry 27:8939-44
Ryan, R J; Charlesworth, M C; McCormick, D J et al. (1988) The glycoprotein hormones: recent studies of structure-function relationships. FASEB J 2:2661-9
Keutmann, H T; Charlesworth, M C; Mason, K A et al. (1987) A receptor-binding region in human choriogonadotropin/lutropin beta subunit. Proc Natl Acad Sci U S A 84:2038-42
Amir, S M; Kubota, K; Tramontano, D et al. (1987) The carbohydrate moiety of bovine thyrotropin is essential for full bioactivity but not for receptor recognition. Endocrinology 120:345-52
Ryan, R J; Keutmann, H T; Charlesworth, M C et al. (1987) Structure-function relationships of gonadotropins. Recent Prog Horm Res 43:383-429
Calvo, F O; Keutmann, H T; Bergert, E R et al. (1986) Deglycosylated human follitropin: characterization and effects on adenosine cyclic 3',5'-phosphate production in porcine granulosa cells. Biochemistry 25:3938-43

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