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Water Sculpts the Distinctive Shapes and Dynamics of the Tumor-Associated Carbohydrate Tn Antigens: Implications for Their Molecular Recognition.
Bermejo, Iris A; Usabiaga, Imanol; Compañón, Ismael; Castro-López, Jorge; Insausti, Aran; Fernández, José A; Avenoza, Alberto; Busto, Jesús H; Jiménez-Barbero, Jesús; Asensio, Juan L; Peregrina, Jesús M; Jiménez-Osés, Gonzalo; Hurtado-Guerrero, Ramón; Cocinero, Emilio J; Corzana, Francisco.
Afiliação
  • Bermejo IA; Departamento de Química, Centro de Investigación en Síntesis Química , Universidad de La Rioja , 26006 Logroño , Spain.
  • Usabiaga I; Departamento de Química Física, Facultad de Ciencia y Tecnología , Universidad del País Vasco (UPV-EHU), 48080 Bilbao , Spain.
  • Compañón I; Departamento de Química, Centro de Investigación en Síntesis Química , Universidad de La Rioja , 26006 Logroño , Spain.
  • Castro-López J; Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza , BIFI-IQFR (CSIC), 50018 Zaragoza , Spain.
  • Insausti A; Departamento de Química Física, Facultad de Ciencia y Tecnología , Universidad del País Vasco (UPV-EHU), 48080 Bilbao , Spain.
  • Fernández JA; Biofisika Institute (CSIC, UPV/EHU), University of the Basque Country (UPV/EHU), 48940 Leioa , Spain.
  • Avenoza A; Departamento de Química Física, Facultad de Ciencia y Tecnología , Universidad del País Vasco (UPV-EHU), 48080 Bilbao , Spain.
  • Busto JH; Departamento de Química, Centro de Investigación en Síntesis Química , Universidad de La Rioja , 26006 Logroño , Spain.
  • Jiménez-Barbero J; Departamento de Química, Centro de Investigación en Síntesis Química , Universidad de La Rioja , 26006 Logroño , Spain.
  • Asensio JL; CIC bioGUNE , Bizkaia Technology Park, Building 801A , 48170 Derio , Spain.
  • Peregrina JM; Ikerbasque , Basque Foundation for Science , Maria Diaz de Haro 13 , 48009 Bilbao , Spain.
  • Jiménez-Osés G; Department of Organic Chemistry II, Faculty of Science & Technology , University of the Basque Country , 48940 Leioa , Spain.
  • Hurtado-Guerrero R; Instituto de Química Orgánica General , IQOG-CSIC. 28006 Madrid , Spain.
  • Cocinero EJ; Departamento de Química, Centro de Investigación en Síntesis Química , Universidad de La Rioja , 26006 Logroño , Spain.
  • Corzana F; Departamento de Química, Centro de Investigación en Síntesis Química , Universidad de La Rioja , 26006 Logroño , Spain.
J Am Chem Soc ; 140(31): 9952-9960, 2018 08 08.
Article em En | MEDLINE | ID: mdl-30004703
ABSTRACT
The tumor-associated carbohydrate Tn antigens include two variants, αGalNAc- O-Thr and αGalNAc- O-Ser. In solution, they exhibit dissimilar shapes and dynamics and bind differently to the same protein receptor. Here, we demonstrate experimentally and theoretically that their conformational preferences in the gas phase are highly similar, revealing the essential role of water. We propose that water molecules prompt the rotation around the glycosidic linkage in the threonine derivative, shielding its hydrophobic methyl group and allowing an optimal solvation of the polar region of the antigen. The unusual arrangement of αGalNAc- O-Thr features a water molecule bound into a "pocket" between the sugar and the threonine. This mechanism is supported by trapping, for the first time, such localized water in the crystal structures of an antibody bound to two glycopeptides that comprise fluorinated Tn antigens in their structure. According to several reported X-ray structures, installing oxygenated amino acids in specific regions of the receptor capable of displacing the bridging water molecule to the bulk-solvent may facilitate the molecular recognition of the Tn antigen with threonine. Overall, our data also explain how water fine-tunes the 3D structure features of similar molecules, which in turn are behind their distinct biological activities.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Água / Antígenos Glicosídicos Associados a Tumores Tipo de estudo: Risk_factors_studies Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Água / Antígenos Glicosídicos Associados a Tumores Tipo de estudo: Risk_factors_studies Idioma: En Ano de publicação: 2018 Tipo de documento: Article