{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:50:26Z","timestamp":1773665426715,"version":"3.50.1"},"reference-count":78,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T00:00:00Z","timestamp":1470614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union (FEDER funds POCI\/01\/0145\/FEDER\/007728) and National Funds (FCT\/MEC, Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia and Minist\u00e9rio da Educa\u00e7\u00e3o e Ci\u00eancia)","award":["Partnership Agreement PT2020  UID\/MULTI\/04378\/2013.UID\/MULTI\/04378\/2013"],"award-info":[{"award-number":["Partnership Agreement PT2020  UID\/MULTI\/04378\/2013.UID\/MULTI\/04378\/2013"]}]},{"name":"Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)","award":["NORTE-01-0145-FEDER-000024"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000024"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["EXCL-II\/QEQ-COM\/0394\/2012"],"award-info":[{"award-number":["EXCL-II\/QEQ-COM\/0394\/2012"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["SFRH\/BD\/84016\/2012"],"award-info":[{"award-number":["SFRH\/BD\/84016\/2012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Glutamine synthetase (GS) is a crucial enzyme to the nitrogen cycle with great commercial and pharmaceutical value. Current inhibitors target the active site, affecting GS activity indiscriminately in all organisms. As the active site is located at the interface between two monomers, the protein-protein interface (PPI) of GSs gains a new role, by providing new targets for enzyme inhibition. Exploring GSs PPI could allow for the development of inhibitors selective for specific organisms. Here we map the PPI of three GSs\u2014human (hsGS), maize (zmGS) and Mycobacterium tuberculosis (mtGS)\u2014and unravel new drugable pockets. Methods: The PPI binding free energy coming from key residues on three GSs from different organisms were mapped by computational alanine scan mutagenesis, applying a multiple dielectric constant MM-PBSA methodology. The most relevant residues for binding are referred as hot-spots. Drugable pockets on GS were detected with the Fpocket software. Results and Conclusions: A total of 23, 19 and 30 hot-spots were identified on hsGS, zmGS and mtGS PPI. Even possessing differences in the hot-spots, hsGS and zmGS PPI are overall very similar. On the other hand, mtGS PPI differs greatly from hsGS and zmGS PPI. A novel drugable pocket was detected on the mtGS PPI. It seems particularly promising for the development of selective anti-tuberculosis drugs given its location on a PPI region that is highly populated with hot-spots and is completely different from the hsGS and zmGS PPIs. Drugs targeting this pockets should be inactive on eukaryotic GS II enzymes.<\/jats:p>","DOI":"10.3390\/molecules21081028","type":"journal-article","created":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T10:14:38Z","timestamp":1470651278000},"page":"1028","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets"],"prefix":"10.3390","volume":"21","author":[{"given":"C\u00e1tia","family":"Moreira","sequence":"first","affiliation":[{"name":"UCIBIO, REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, 4169-007 Porto, Portugal"}]},{"given":"Maria","family":"Ramos","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, 4169-007 Porto, Portugal"}]},{"given":"Pedro","family":"Fernandes","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2016,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1073\/pnas.73.2.476","article-title":"Mechanistic studies of glutamine synthetase from Escherichia coli: Kinetic evidence for two reaction intermediates in biosynthetic reaction","volume":"73","author":"Rhee","year":"1976","journal-title":"Proc. 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