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United States Department of Agriculture

Agricultural Research Service

Title: Consensus Chemistry and Beta-Turn Conformation of the Active Core of the Myotropic/diuretic Insect Kinin Neuropeptide Family from Experimental and Computational Analysis

Authors
item Roberts, Victoria - SCRIPPS RESEARCH INST.
item Nachman, Ronald
item Coast, Geoff - UNIVERSITY OF LONDON
item Hariharan, Meena - SCRIPPS RESEARCH INST.
item Chung, Jum - UNIVERSITY OF LONDON
item Holman, G
item Tainer, John - SCRIPPS RESEARCH INST.

Submitted to: Journal of Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 17, 1997
Publication Date: N/A

Interpretive Summary: Because of the problems with the development of resistance to conventional chemical control procedures for many major pest species, there is a critical need for new concepts and alternative approaches in controlling such pests. The basic premise of this research is that peptides serve as internal messengers in insects to regulate vital functions. The neuropeptides addressed in this report are the insect kinins, which have been implicated in digestive and water balance processes. However, the peptides themselves are unsuitable for control measures due to their instability to insect digestive enzymes and environmental factors. New, selective control measures may be developed by designing chemicals that actively inhibit or stimulate peptide regulated functions, resulting in disruption of the internal environment of the insect. However, the design of non-peptide mimics requires a knowledge of the active, three dimensional lstructure that these peptides attain at their site of action. In their natural state, peptides generally rotate freely in solution, adopting no particular shape. By the use of a combination of experimental and theoretical molecular modeling techniques, we have determined the active three dimensional shape of a peptide analog of the insect kinin neuropeptide family with chemically designed rigidity. This shape could in turn serve as a template to design non-peptide mimics with control potentials. Thus, the study not only adds to the scientific body of knowledge, but may lead to practical solutions to the problems posed by destructive insects.

Technical Abstract: The structural requirements of the insect kinin neuropeptides for receptor binding have been determined using an interdisciplinary approach combining structure/activity studies with conformational search techniques. The kinin neuropeptides show activity in two biological assays, one based on myotropic (muscle contractile) activity and the other on diuretic activity. .The C-terminal pentapeptide sequence of the insect kinins, Phe**1-X**2- X**3-Trp**4-Gly**5-NH2 (X**2 = Asn, His, Tyr, Ser; X**3 = Ser, Pro) retains full biological activity. Systematic Ala substitutions of this pentapeptide active core gave similar activity profiles in both assays, suggesting that the insect kinins bind to two distinct receptors in similar conformations. Molecular dynamics simulations of active core peptides indicated a shared beta-turn structure for both X**3 = Ser and X**3 = Pro. An end-to-end cyclic hexapeptide, cyclo[Phe-Phe-Pro-Trp-Gly-Ala], was designed to lock in this turn conformation. The lowest energy structure o the cyclic peptide found for the linear active core and contained a type VI turn with Pro in the i+2 position preceded by a cis peptide bond. A higher energy conformation was found with Pro residue in the i+1 position of a beta-turn preceded by a trans peptide bond. NMR spectra from the cyclic analog were consistent with computational search results and revealed a 3:2 ratio of cis:trans Pro structures in solution. Although the cyclic analog displayed decreased activity relative to a highly active linear analog, it showed stronger binding to the diuretic receptor. Linear active core analogs with modified C-terminii also displayed strong binding to the diuretic receptor, suggesting that the C-terminus is important for signal transduction of the biological message.

Last Modified: 7/28/2014
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