Modeling kinase–substrate specificity: implication of the distance between substrate nucleophilic oxygen and attacked phosphorus of ATP analog on binding affinity

Sun, Mei; Xiao-hong, Liu; Ji, Sanhao; Zhao, Yufen

doi:10.1016/j.jmgm.2004.12.003

Cited by 3 publications

(2 citation statements)

References 36 publications

(37 reference statements)

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“…Molecular modeling allowed us to predict that the distance between the oxygen of NCK SH3 Tyr OH group and the γ phosphorous atom of ATP varied between 2.7 and 8.6 Å. Previous molecular modeling simulations on kinase-substrate complexes highlighted that for efficiently phosphorylated substrates, the distance between substrate nucleophilic oxygen and attacked phosphorus of the ATP molecule is close to 3.3 Å, a value corresponding to the van der Waals sum of oxygen and phosphorus radii (Sun et al, 2005). Strikingly, our modeling predicted very similar distances for the EPHA4-NCK complexes (NCK1: 2.7 Å and NCK2: 3.6 Å).…”

Section: Discussionmentioning

confidence: 99%

“…It is also notable that the 5.2 Å distance predicted for NCK2 SH3-2/3 is similar to the previously reported distance of 5.0 Å for the insulin receptor RTK and its substrate (Hubbard, 1997). A distance of up to 9.8 Å was also estimated for poorer substrates (Sun et al, 2005). Consequently, it appears that the range of distances determined here is reasonable for a kinase-substrate interaction.…”

Section: Discussionmentioning

confidence: 99%

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Direct Phosphorylation of SRC Homology 3 Domains by Tyrosine Kinase Receptors Disassembles Ligand-Induced Signaling Networks

et al. 2018

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Phosphotyrosine (pTyr) signaling has evolved into a key cell-to-cell communication system. Activated receptor tyrosine kinases (RTKs) initiate several pTyr-dependent signaling networks by creating the docking sites required for the assembly of protein complexes. However, the mechanisms leading to network disassembly and its consequence on signal transduction remain essentially unknown. We show that activated RTKs terminate downstream signaling via the direct phosphorylation of an evolutionarily conserved Tyr present in most SRC homology (SH) 3 domains, which are often part of key hub proteins for RTK-dependent signaling. We demonstrate that the direct EPHA4 RTK phosphorylation of adaptor protein NCK SH3s at these sites results in the collapse of signaling networks and abrogates their function. We also reveal that this negative regulation mechanism is shared by other RTKs. Our findings uncover a conserved mechanism through which RTKs rapidly and reversibly terminate downstream signaling while remaining in a catalytically active state on the plasma membrane.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Direct Phosphorylation of SRC Homology 3 Domains by Tyrosine Kinase Receptors Disassembles Ligand-Induced Signaling Networks

et al. 2018

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Substrate screening of protein kinases: Detection methods and combinatorial peptide libraries

et al. 2010

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The study of protein kinases has become a matter of great importance in the development of new drugs for the treatment of diseases, including cancer and inflammation. Substrate screening is the first step in the fundamental investigation of protein kinases and the development of inhibitors for use in drug discovery. Towards this goal, various studies have been reported regarding the development of phospho-peptide detection methods and the screening of phosphorylated peptide sites by protein kinases. This review introduces the detection methods for phosphorylation events using the reagents with (γ(32)P)ATP, ligand-linked ATP, phospho-peptide-specific antibodies and metal chelating compounds. Chemical modification methods using β-elimination for the detection of phospho-Ser/Thr peptides are introduced as well. In addition, the implementations of combinatorial peptide libraries for screening peptide substrates of protein kinases are discussed. The phage display approach has been suggested as an alternative method of using synthetic peptides for screening the substrate specificities of protein kinase. However, a solid phase assay using a peptide library-bound polymer resin or a peptide-arrayed glass chip is preferred for high throughput screening (HTS).

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Substrate specificity of protein kinases and computational prediction of substrates

Kobe

Kampmann

Forwood

et al. 2005

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Modeling kinase–substrate specificity: implication of the distance between substrate nucleophilic oxygen and attacked phosphorus of ATP analog on binding affinity

Cited by 3 publications

References 36 publications

Direct Phosphorylation of SRC Homology 3 Domains by Tyrosine Kinase Receptors Disassembles Ligand-Induced Signaling Networks

Direct Phosphorylation of SRC Homology 3 Domains by Tyrosine Kinase Receptors Disassembles Ligand-Induced Signaling Networks

Substrate screening of protein kinases: Detection methods and combinatorial peptide libraries

Substrate specificity of protein kinases and computational prediction of substrates

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