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Targeting cysteine rich C1 domain of Scaffold protein Kinase Suppressor of Ras (KSR) with anthocyanidins and flavonoids - a binding affinity characterization study.

Karthik D, Majumder P, Palanisamy S, Khairunnisa K, Venugopal V - Bioinformation (2014)

Bottom Line: In that perspective the cysteine rich C1 domain of scaffold proteins kinase suppressor of Ras-1 was targeted rather than its ATP binding site with small ligand molecules like flavones and anthocyanidins and analyzed through insilico docking studies.The binding energy evaluation shows the importance of hydroxyl groups at various positions on the flavone and anthocyanidin nucleus.Over all binding interaction shows these ligands occupied the potential sites of cysteine rich C1 domain of scaffold protein KSR.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Amrita School of Pharmacy, AIMS Health Science Campus, Amrita Vishwa Vidyapeetham University, Kochi, Kerala, India.

ABSTRACT
Kinase Suppressor of Ras (KSR) is a molecular scaffold that interacts with the core kinase components of the ERK cascade, Raf, MEK, ERK to provide spatial and temporal regulation of Ras-dependent ERK cascade signaling. Interruption of this mechanism can have a high influence in inhibiting the downstream signaling of the mutated tyrosine kinase receptor kinase upon ligand binding. Still none of the studies targeted to prevent the binding of Raf, MEK binding on kinase suppressor of RAS. In that perspective the cysteine rich C1 domain of scaffold proteins kinase suppressor of Ras-1 was targeted rather than its ATP binding site with small ligand molecules like flavones and anthocyanidins and analyzed through insilico docking studies. The binding energy evaluation shows the importance of hydroxyl groups at various positions on the flavone and anthocyanidin nucleus. Over all binding interaction shows these ligands occupied the potential sites of cysteine rich C1 domain of scaffold protein KSR.

No MeSH data available.


A) The schematic diagram shows the domains of knase suppressor of Ras with their terminals. The cysteine rich C1 domain − CA3 is emphasized to show their protein structure makup. The marking ( ) shown in the image indicates the respective beta sheets; B) Secondary structure showing the beta sheets (β1, β2, β3, β4, β5) containing amino acid residue at the gorge. The mesh diagram with encircled areas shows the gorge of KSR C1 domain. (Images have been visualized using Accelrys discovery studio 4.0 and Pymol viewer). The schematic diagram is created based on the information as per the literature.
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Figure 1: A) The schematic diagram shows the domains of knase suppressor of Ras with their terminals. The cysteine rich C1 domain − CA3 is emphasized to show their protein structure makup. The marking ( ) shown in the image indicates the respective beta sheets; B) Secondary structure showing the beta sheets (β1, β2, β3, β4, β5) containing amino acid residue at the gorge. The mesh diagram with encircled areas shows the gorge of KSR C1 domain. (Images have been visualized using Accelrys discovery studio 4.0 and Pymol viewer). The schematic diagram is created based on the information as per the literature.

Mentions: Kinase Suppressor of Ras (KSR1) is a molecular scaffold that interacts with the core kinase components of the ERK cascade, Raf, MEK, and ERK and provides spatial and temporal regulation of Ras-dependent ERK cascade signaling. CK2 is a component of the KSR1 scaffold complex that contributes to Raf kinase activation [10]. Raf-1 is a ceramide-activated kinase and that its C1 domain is involved in the ceramide-mediated response, Whereas KSR1 and its C1 domain is not getting activated in the same manner [11]. Unlike Raf-1, however, the kinase domain of KSR1 appears to be non-functional, suggesting that KSR-1 does not promote Ras signaling by phosphorylating target molecules [12,13,14]. So instead of targeting kinase domain, ligands directed at the cysteine rich C1 domain would have better functional activity in preventing Ras signaling upon inducing conformational changes along the scaffold protein preventing Raf-1, ERK binding to their site on KSR1. The crystal structure of cysteine rich C1 domain of kinase suppressor of Ras is shown in the (Figure 1). The conserved KSR1 domains include a 40 residue region unique to KSR1 proteins (CA1), a proline-rich region (CA2), a cysteinerich C1 domain (CA3), a serine/threonine-rich region (CA4), and a putative kinase domain (CA5). Similar to the domain organization of Raf-1, the smaller conserved domains of KSR1 are found in the N-terminal region, while the kinase-like domain occupies the C-terminal half of the protein. Unlike Raf1, however, the kinase domain of KSR1 appears to be nonfunctional, suggesting that KSR1 does not promote Ras signaling by phosphorylating target molecules. C1 domains are defined as regions of approximately 50 amino acid residues that contain the motif HX10-12CX2CX11-19CX2CX4 HX2-4CX5-9C [15]. C1A and C1B are the two repeat C1 domains located within the same protein. C1 domains were initially identified as the phorbol ester and 1, 2-dialyglycerol binding moieties of the protein kinase C (PKC) family of serine/ threonine kinases [16]. Ligands antagonizing the KSR1 scaffold activity and thereby interrupting the MAPK signaling pathway are not available yet. But researches were started focusing on to analyse its potential in binding with small molecules like flavonoids and other phytoconstituents. Present study focuses on binding affinity of some selected anthocyanidins and flavones on the basis of existing reviews [17]. Rare flavonoids like 2'-Hydroxygenistein was found to occupy the Raf binding site of KSR [18].


Targeting cysteine rich C1 domain of Scaffold protein Kinase Suppressor of Ras (KSR) with anthocyanidins and flavonoids - a binding affinity characterization study.

Karthik D, Majumder P, Palanisamy S, Khairunnisa K, Venugopal V - Bioinformation (2014)

A) The schematic diagram shows the domains of knase suppressor of Ras with their terminals. The cysteine rich C1 domain − CA3 is emphasized to show their protein structure makup. The marking ( ) shown in the image indicates the respective beta sheets; B) Secondary structure showing the beta sheets (β1, β2, β3, β4, β5) containing amino acid residue at the gorge. The mesh diagram with encircled areas shows the gorge of KSR C1 domain. (Images have been visualized using Accelrys discovery studio 4.0 and Pymol viewer). The schematic diagram is created based on the information as per the literature.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: A) The schematic diagram shows the domains of knase suppressor of Ras with their terminals. The cysteine rich C1 domain − CA3 is emphasized to show their protein structure makup. The marking ( ) shown in the image indicates the respective beta sheets; B) Secondary structure showing the beta sheets (β1, β2, β3, β4, β5) containing amino acid residue at the gorge. The mesh diagram with encircled areas shows the gorge of KSR C1 domain. (Images have been visualized using Accelrys discovery studio 4.0 and Pymol viewer). The schematic diagram is created based on the information as per the literature.
Mentions: Kinase Suppressor of Ras (KSR1) is a molecular scaffold that interacts with the core kinase components of the ERK cascade, Raf, MEK, and ERK and provides spatial and temporal regulation of Ras-dependent ERK cascade signaling. CK2 is a component of the KSR1 scaffold complex that contributes to Raf kinase activation [10]. Raf-1 is a ceramide-activated kinase and that its C1 domain is involved in the ceramide-mediated response, Whereas KSR1 and its C1 domain is not getting activated in the same manner [11]. Unlike Raf-1, however, the kinase domain of KSR1 appears to be non-functional, suggesting that KSR-1 does not promote Ras signaling by phosphorylating target molecules [12,13,14]. So instead of targeting kinase domain, ligands directed at the cysteine rich C1 domain would have better functional activity in preventing Ras signaling upon inducing conformational changes along the scaffold protein preventing Raf-1, ERK binding to their site on KSR1. The crystal structure of cysteine rich C1 domain of kinase suppressor of Ras is shown in the (Figure 1). The conserved KSR1 domains include a 40 residue region unique to KSR1 proteins (CA1), a proline-rich region (CA2), a cysteinerich C1 domain (CA3), a serine/threonine-rich region (CA4), and a putative kinase domain (CA5). Similar to the domain organization of Raf-1, the smaller conserved domains of KSR1 are found in the N-terminal region, while the kinase-like domain occupies the C-terminal half of the protein. Unlike Raf1, however, the kinase domain of KSR1 appears to be nonfunctional, suggesting that KSR1 does not promote Ras signaling by phosphorylating target molecules. C1 domains are defined as regions of approximately 50 amino acid residues that contain the motif HX10-12CX2CX11-19CX2CX4 HX2-4CX5-9C [15]. C1A and C1B are the two repeat C1 domains located within the same protein. C1 domains were initially identified as the phorbol ester and 1, 2-dialyglycerol binding moieties of the protein kinase C (PKC) family of serine/ threonine kinases [16]. Ligands antagonizing the KSR1 scaffold activity and thereby interrupting the MAPK signaling pathway are not available yet. But researches were started focusing on to analyse its potential in binding with small molecules like flavonoids and other phytoconstituents. Present study focuses on binding affinity of some selected anthocyanidins and flavones on the basis of existing reviews [17]. Rare flavonoids like 2'-Hydroxygenistein was found to occupy the Raf binding site of KSR [18].

Bottom Line: In that perspective the cysteine rich C1 domain of scaffold proteins kinase suppressor of Ras-1 was targeted rather than its ATP binding site with small ligand molecules like flavones and anthocyanidins and analyzed through insilico docking studies.The binding energy evaluation shows the importance of hydroxyl groups at various positions on the flavone and anthocyanidin nucleus.Over all binding interaction shows these ligands occupied the potential sites of cysteine rich C1 domain of scaffold protein KSR.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Amrita School of Pharmacy, AIMS Health Science Campus, Amrita Vishwa Vidyapeetham University, Kochi, Kerala, India.

ABSTRACT
Kinase Suppressor of Ras (KSR) is a molecular scaffold that interacts with the core kinase components of the ERK cascade, Raf, MEK, ERK to provide spatial and temporal regulation of Ras-dependent ERK cascade signaling. Interruption of this mechanism can have a high influence in inhibiting the downstream signaling of the mutated tyrosine kinase receptor kinase upon ligand binding. Still none of the studies targeted to prevent the binding of Raf, MEK binding on kinase suppressor of RAS. In that perspective the cysteine rich C1 domain of scaffold proteins kinase suppressor of Ras-1 was targeted rather than its ATP binding site with small ligand molecules like flavones and anthocyanidins and analyzed through insilico docking studies. The binding energy evaluation shows the importance of hydroxyl groups at various positions on the flavone and anthocyanidin nucleus. Over all binding interaction shows these ligands occupied the potential sites of cysteine rich C1 domain of scaffold protein KSR.

No MeSH data available.