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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Crystal structures of the apo form and a complex of human LMW-PTP with a phosphonic acid provide new evidence of a secondary site potentially related to the anchorage of natural substrates

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Fonseca, Emanuella M. B. [1] ; Trivella, Daniela B. B. [2, 1] ; Scorsato, Valeria [1] ; Dias, Mariana P. [1] ; Bazzo, Natalia L. [1] ; Mandapati, Kishore R. [2, 1] ; de Oliveira, Fabio L. [1] ; Ferreira-Halder, Carmen V. [3] ; Pilli, Ronaldo A. [2] ; Miranda, Paulo C. M. L. [2] ; Aparicio, Ricardo [1]
Total Authors: 11
[1] Univ Estadual Campinas, Inst Chem, Lab Struct Biol & Crystallog, BR-13083970 Campinas, SP - Brazil
[2] Univ Estadual Campinas, Inst Chem, Dept Organ Chem, BR-13083970 Campinas, SP - Brazil
[3] Univ Estadual Campinas, Inst Biol, Dept Biochem, BR-13083862 Campinas, SP - Brazil
Total Affiliations: 3
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry; v. 23, n. 15, p. 4462-4471, AUG 1 2015.
Web of Science Citations: 4

Low molecular weight protein tyrosine phosphatases (LMW-PTP, EC are a family of single-domain enzymes with molecular weight up to 18 kDa, expressed in different tissues and considered attractive pharmacological targets for cancer chemotherapy. Despite this, few LMW-PTP inhibitors have been described to date, and the structural information on LMW-PTP druggable binding sites is scarce. In this study, a small series of phosphonic acids were designed based on a new crystallographic structure of LMW-PTP complexed with benzylsulfonic acid, determined at 2.1 angstrom. In silico docking was used as a tool to interpret the structural and enzyme kinetics data, as well as to design new analogs. From the synthesized series, two compounds were found to act as competitive inhibitors, with inhibition constants of 0.124 and 0.047 mM. We also report the 2.4 angstrom structure of another complex in which LMW-PTP is bound to benzylphosphonic acid, and a structure of apo LMW-PTP determined at 2.3 angstrom resolution. Although no appreciable conformation changes were observed, in the latter structures, amino acid residues from an expression tag were found bound to a hydrophobic region at the protein surface. This regions is neighbored by positively charged residues, adjacent to the active site pocket, suggesting that this region might be not a mere artefact of crystal contacts but an indication of a possible anchoring region for the natural substrate-which is a phosphorylated protein. (C) 2015 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 10/17544-5 - Structural and molecular bases of inhibitor recognition by the CDC-25 and LMW-PTP human protein phosphatases involved in cancer
Grantee:Daniela Barretto Barbosa Trivella
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 11/03054-9 - Structural characterization of the human phosphatases PTP-1B and PP2A, involved in cancer, and their interactions with inhibitors
Grantee:Valeria Scorsato
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 09/51602-5 - Chemical biology: new natural and synthetic molecular targets against cancer, structural studies, biological evaluation and mode of action
Grantee:Ronaldo Aloise Pilli
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 11/15792-4 - New inhibitors of LMW-PTP and CDC25B: fragment-based drug design using in silico methods, inhibition assays and Protein Crystallography
Grantee:Emanuella Maria Barreto Fonseca
Support Opportunities: Scholarships in Brazil - Doctorate