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Resolving mechanistic details of peptide transport across membranes using crystallographic and non-crystallographic structural biology approaches

Grant number: 15/50366-7
Support type:Regular Research Grants
Duration: November 01, 2015 - October 31, 2020
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Cooperation agreement: BBSRC, UKRI
Principal Investigator:Antonio José da Costa Filho
Grantee:Antonio José da Costa Filho
Principal investigator abroad: Anthony Watts
Institution abroad: University of Oxford, England
Home Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Extending our recent new crystallographic structural models, ESR DEER and MD (Fowler et al., (2015) Structure, 23(2):290- 301 - front cover feature), we now aim to define the reaction coordinates for two peptide transporters from the bacteria Shewanella oniedensis (PepTSo) and from Streptococcus thermophilus (PepTSt). Both the conformational changes associated with discernible Intermediates in the transporter pathway(s), as well as the lipid dependence of the various stages are currently not described, and so will be addressed here using underpinning molecular biology approaches in Oxford and Sao Paulo. The response of the transporter to the proton motive force (pmf) in sealed systems, and the nature of the ligand binding environment, will also be examined, giving new Information about direct coupung of peptide transport to the energetics that drives function, with a view to defining electromechanical coupling within this important drug facilitator. To do this we will: - direct the design of spectroscopic studies of membrane-embedded peptide transporters using currently available, as well as new crystal structural and MD generated models; - use the spectroscopic and functional Information to determine conformational and dynamic details of membrane- embedded transporters, and generate novel detailed molecular models of reaction intermediates; With a final goal of describing the mechanism of action, lipid dependence and conformations of reaction intermediate states of peptide (and other homologues) transporters in molecular and kinetic detail. (AU)

Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
REDDY, S. THIRUPATHI; UVERSKY, VLADIMIR N.; COSTA-FILHO, ANTONIO JOSE. Nucleation-dependent amyloid fibrillation of human GRASP55 in aqueous solution. EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, v. 49, n. 2, p. 133-143, MAR 2020. Web of Science Citations: 0.
ALVAREZ, NATALIA; VINA, DIANA; LEITE, CELISNOLIA M.; MENDES, LUIS F. S.; BATISTA, ALZIR A.; ELLENA, JAVIER; COSTA-FILHO, ANTONIO J.; FACCHIN, GIANELLA. Synthesis and structural characterization of a series of ternary copper(II)-L-dipeptide-neocuproine complexes. Study of their cytotoxicity against cancer cells including MDA-MB-231, triple negative breast cancer cells. Journal of Inorganic Biochemistry, v. 203, FEB 2020. Web of Science Citations: 0.
MENDES, LUIS FELIPE S.; BATISTA, MARIANA R. B.; JUDGE, PETER J.; WATTS, ANTHONY; REDFIELD, CHRISTINA; COSTA-FILHO, ANTONIO J. Conformational flexibility of GRASPs and their constituent PDZ subdomains reveals structural basis of their promiscuous interactome. FEBS Journal, JAN 2020. Web of Science Citations: 0.
BATISTA, MARIANA R. B.; WATTS, ANTHONY; COSTA-FILHO, ANTONIO JOSE. Exploring Conformational Transitions and Free-Energy Profiles of Proton-Coupled Oligopeptide Transporters. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, v. 15, n. 11, p. 6433-6443, NOV 2019. Web of Science Citations: 0.
MENDES, LUIS F. S.; FONTANA, NATALIA A.; OLIVEIRA, CAROLINA G.; FREIRE, MARJORIE C. L. C.; LOPES, JOSE L. S.; MELO, FERNANDO A.; COSTA-FILHO, ANTONIO J. The GRASP domain in golgi reassembly and stacking proteins: differences and similarities between lower and higher Eukaryotes. FEBS Journal, v. 286, n. 17, p. 3340-3358, SEP 2019. Web of Science Citations: 2.
THIRUPATHI REDDY, S.; SANTOS MENDES, LUIS FELIPE; FONTANA, NATALIA APARECIDA; COSTA-FILHO, ANTONIO JOSE. Exploring structural aspects of the human Golgi matrix protein GRASP55 in solution. International Journal of Biological Macromolecules, v. 135, p. 481-489, AUG 15 2019. Web of Science Citations: 0.
FONTANA, N. A.; FONSECA-MALDONADO, R.; MENDES, L. F. S.; MELEIRO, L. P.; COSTA-FILHO, A. J. The yeast GRASP Grh1 displays a high polypeptide backbone mobility along with an amyloidogenic behavior. SCIENTIFIC REPORTS, v. 8, OCT 24 2018. Web of Science Citations: 3.
MENDES, LUIS F. S.; BASSO, LUIS G. M.; KUMAGAI, PATRICIA S.; FONSECA-MALDONADO, RAQUEL; COSTA-FILHO, ANTONIO J. Disorder-to-order transitions in the molten globule-like Golgi Reassembly and Stacking Protein. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1862, n. 4, p. 855-865, APR 2018. Web of Science Citations: 4.
MICHELETTO, MARIANA C.; MENDES, LUIS F. S.; BASSO, LUIS G. M.; FONSECA-MALDONADO, RAQUEL G.; COSTA-FILHO, ANTONIO J. Lipid membranes and acyl-CoA esters promote opposing effects on acyl-CoA binding protein structure and stability. International Journal of Biological Macromolecules, v. 102, p. 284-293, SEP 2017. Web of Science Citations: 2.

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