Peptides are essential for many biological processes,
acting as hormones, neurotransmitters, enzyme substrates
and inhibitors, neuromodulating agents and immunomodulators.
Because peptides themselves are susceptible to degradation,
exhibit poor bioavailability, poor solubility, or
the discovery of nonpeptide molecules that mimic or block peptide
function is necessary to provide lead compounds for drug development.
Finding the biologically active structure of a peptide
would greatly assist the search for mimics and inhibitors.
Peptides are flexible molecules, so
a peptide conformation found by nuclear magnetic resonance (NMR)
or X-ray crystallography need not necessarily
resemble the biologically active, receptor-bound conformation.
However, combining activity data from related neuropeptides and
their analogs with determination of shared conformational preferences
provides a rational basis for
probing receptor structure and designing
conformationally restricted agonists and antagonists.
We are investigating the structures of neuropeptides isolated
from insects, which control diverse functions including
stimulating smooth muscle contractions, pheromone
biosynthesis, and diuretic activity.
Fragments of these peptides, usually five to ten amino
acid residues, retain full biological activity and are small
enough to examine computationally.
Many of these insect neuropeptides are related
in sequence to mammalian peptides, suggesting there are
families of peptides that span many organisms.
Therefore, information about biologically active conformations
determined for insect neuropeptides is likely to be relevant
to related neuropeptides found in humans, which display
medically important functions, such as inflammation and
We have also investigated the effects of protein structure
on a peptide in studies on catalytic antibodies.
- Smithrud, D. B., Benkovic, P. A., Benkovic, S. J.,
Roberts, V. A., Liu, J., Iwama, S., Phillips, B. W., Neagu, I.,
Smith, A. B., III, Hirschmann, R., (2000)
"Cyclic Peptide Formation Catalyzed by an Antibody Ligase",
Proc. Natl. Acad. Sci, USA, 97, 1953-1958.
- Roberts, V. A., Nachman, R. J., Coast, G. M., Hariharan, M., Chung, J.
S., Holman, G. M., and Tainer, J. A., (1997) "Consensus Chemistry and
beta-Turn Conformation of the Active Core of the Insect Kinin Neuropeptide
Family", Chemistry & Biology, 4, 105-117.
- Nachman, R.J., Olender, E.H., Roberts, V.A., Holman, G.M., and
Yamamoto, D., (1996) "A Nonpeptidal Peptidomimetic Agonist of the
Insect FLRFamide Myosuppressin Family", Peptides, 17,
- Nachman, R. J., Roberts, V. A., Holman, G. M., and Beier, R. C., (1995)
"Pseudodipeptide Analogs of the Pyrokinin/PBAN (FXPRLa) Insect
Neuropeptide Family Containing Carbocyclic Pro-Mimetic Conformational
Components", Reg. Pep., 57, 359-370.
- Bell, C. W., Roberts, V. A., Scholthof, K.-B. G., Zhang, G., and Karu,
A. E., (1995) "Recombinant Antibodies to Diuron: A Model for the
Phenylurea Combining Site", in Immunoanalysis of Agrochemicals,
Emerging Technologies, Nelson, J. O., Karu, A. E., and Wong, R. B.,
eds., American Chemical Society, Washington D. C., 50-71.
- Friedman, A. R., Roberts, V. A., and Tainer, J. A., (1994)
"Predicting Molecular Interactions and Inducible Complementarity:
Fragment Docking of Fab-Peptide Complexes", Proteins, 20,
- Nachman, R. J., Kuniyoshi, H., Roberts, V. A., Holman, G. M., and
Suzuki, A., (1993) "Active Conformation of the Pyrokinin/PBAN
Neuropeptide Family for Pheromone Biosynthesis in the Silkmoth Bombyx
mori", Biochem. Biophys. Res. Comm., 193, 661-666.
- Nachman, R. J., Roberts, V. A., Dyson, H. J., Holman, G. M., and
Tainer, J. A., (1991), "The Active Conformation of an Insect
Neuropeptide Family", Proc. Natl. Acad. Sci. USA, 88,