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Preferential Binding of the Marine β‐carboline Manzamine A to the NTDK Domain of RSK1
Author(s) -
Mayer Alejandro,
Hall Mary,
Lach Joseph,
Clifford Jonathan,
Chandrasena Kevin,
Canton Caitlin,
Kontoyianni Maria
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.936.4
Subject(s) - kinase , serine , ribosomal s6 kinase , threonine , chemistry , protein kinase domain , cytosol , phosphorylation , extracellular , docking (animal) , microbiology and biotechnology , biochemistry , biology , enzyme , gene , protein kinase b , mutant , p70 s6 kinase 1 , medicine , nursing
We reported that manzamine A (MZA) inhibited LPS‐treated rat microglia TXB 2 (IC 50 <0.016 µM) and O 2 ‐ (IC 50 =0.1 µM) generation (BMC Pharmacology 5(1) 6, 2005), LPS‐treated human BMΦ TXB 2 (apparent IC 50 <0.7 µM) (Inflam Res. 53(S3): S217, 2004) and rat p90 ribosomal S6 kinase 1 (RSK1) with a 10‐fold selectivity in potency versus RSK2 (IC 50 of 15.01 μM and 108.4 μM, respectively) in biochemical studies (Program 545.5, Society of Neuroscience, 2009). We also hypothesized that MZA's differential binding and selectivity toward RSK1 and RSK2 could be explored by computational docking experiments employing both the N‐terminal (NTDK) and C‐terminal kinase domains (CTKD). Results: The RSK1‐MZA (NTDK and CTKD‐termini) complexes appeared to have stronger interactions and preferable energetics compared to respective RSK2‐MZA complexes. In addition, our computational strategy suggested that MZA bound preferentially to the NTDK domain of RSK1 rather than the CTKD domain. RSK is a vertebrate family of cytosolic serine‐threonine kinases that act downstream of the ras‐ERK1/2 (extracellular‐signal‐regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes including growth, survival and proliferation. Consequently, our findings lead us to hypothesize that there may be additional novel pharmacological properties of MZA and the 80 currently known manzamine‐type alkaloids isolated from several sponge genera. Support by the Office of Research, Midwestern University (AMSM) is gratefully acknowledged.