Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling
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| 008 | 210128e20151101xx s 000 0 eng | ||
| 024 | 7 | 0 | |a 10.1007/s00894-015-2821-z |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s00894-015-2821-z | ||
| 245 | 0 | 0 | |a Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling |h [Elektronische Daten] |c [Oyekanmi Nash, Olaposi Omotuyi, Joonku Lee, Byoung-Mog Kwon, Lucy Ogbadu] |
| 520 | 3 | |a As a key step in achieving low-cost, easily accessible anti-cancer therapy for low- and middle-income countries, we recently established the scientific basis for the folkloric use of Artocarpus altilis for the treatment of cancer by investigating the geranyl dihydrochalcone (CG-901) content and its interference with signal transducer and activator of transcription 3 (STAT3) phosphorylation and blockage of further downstream signaling. In the current study, the CG-901 upstream target was queried by chemical fingerprinting similarity assessment, semi-empirical (PM6ESCF) QMMM and molecular dynamics (MD) simulation. Moderate (∼0.4) to high (∼0.7) Tanimoto scores were found when the CG-901 scaffold was compared to ligands co-crystallized with Janus kinases (JAK) 1-3. High negative energy values were obtained when the CG-901 was treated semi-empirically (PM6ESCF) within the classical field of JAK (1-3). Multiple nanosecond MD simulations showed that CG-901 did not cause any large structural perturbations in the nucleotide-binding, activation and catalytic loops within the kinase (JH1) domain of JAK (1-3); however, it reduced the energy required to attain metastability along the path to energy minima conformation. In comparison to JAK1 and Apo-state JAK2, JAK2-bound CG-901 exhibited a highly re-organized key intra-domain protein network; indicating atomic level interference with inter-residue communication. In conclusion, CG-901 isolated from A. altilis represents a broad-spectrum JAK inhibitor, which may underlie the mechanism of STAT3 phosphorylation blockage. Graphical abstract Upper panel Janus kinase 2 upstream signaling pathway. Lower panel Apo-JAK2 (left) and CG-901-bound JAK2 (right) | |
| 540 | |a Springer-Verlag Berlin Heidelberg, 2015 | ||
| 690 | 7 | |a Artocarpus altilis |2 nationallicence | |
| 690 | 7 | |a Anticancer |2 nationallicence | |
| 690 | 7 | |a STAT3 |2 nationallicence | |
| 690 | 7 | |a Janus kinase |2 nationallicence | |
| 690 | 7 | |a Geranyl dihydrochalcone |2 nationallicence | |
| 690 | 7 | |a Critical nodes |2 nationallicence | |
| 700 | 1 | |a Nash |D Oyekanmi |u Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria |4 aut | |
| 700 | 1 | |a Omotuyi |D Olaposi |u Center for Biocomputing, Adekunle Ajasin University, Akungba-Akoko, Nigeria |4 aut | |
| 700 | 1 | |a Lee |D Joonku |u International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea |4 aut | |
| 700 | 1 | |a Kwon |D Byoung-Mog |u Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea |4 aut | |
| 700 | 1 | |a Ogbadu |D Lucy |u Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria |4 aut | |
| 773 | 0 | |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/11(2015-11-01), 1-11 |x 1610-2940 |q 21:11<1 |1 2015 |2 21 |o 894 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s00894-015-2821-z |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s00894-015-2821-z |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Nash |D Oyekanmi |u Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Omotuyi |D Olaposi |u Center for Biocomputing, Adekunle Ajasin University, Akungba-Akoko, Nigeria |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Lee |D Joonku |u International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Kwon |D Byoung-Mog |u Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Ogbadu |D Lucy |u Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/11(2015-11-01), 1-11 |x 1610-2940 |q 21:11<1 |1 2015 |2 21 |o 894 | ||