peptide
The peptide protein kinase superfamily represents about 2% of the human genome genes and encodes approximately 545 kinases. The eukaryotic protein kinases are cut up into two large classes, the serine/threonine and the tyrosine kinases. The two classes have extensive sequence and structure homologies. The catalytic domain was originally divided into 11 conserved subdomains that are architecturally folded into a small N-terminal lobe and a larger C-terminal lobe.
The N-terminal lobe houses a glycine-rich loop P-loop for ATP binding and C-terminal domain houses a conserved activation loop also referred to as the T-loop or activation segment that is itself subject to phosphorylation control. Phosphorylation takes place in a cleft between the two lobes and the phosphate-donating ATP molecule is trapped in a deep cavity adjacent to the P-loop. The interface of substrate binding is generally big and contains also grooves that are found on the surface of the N- and C-terminal lobes, which provide kinase specificity.
Even though all traditional peptide protein kinases possess a shared catalytic fold, these proteins exhibit considerable variation in their substrate specificity and signal transmission. This is largely due to other factors, including discrete regions positioned outside the catalytic core, regulatory domains, or adaptor molecules that can have a direct impact on the interaction with substrates or other players in the signaling network. Protein kinases are often regulated by protein interactions, typically involving contacts between large globular domains. Evidence indicates that interactions may also be between protein kinases and short linear or linear epitopes that interact with specific docking grooves in the protein kinase and are distinct from the substrate binding site.
PEPTIDES AS COMPETITIVE INHIBITORS
The specificity of peptide protein kinases for stratum phosphorylation is generally based on the major amino acid sequences at once adjacent to the site of phosphorylation, referred to as the consensus sequence. The number and nature of contacts with rest near the phosphorylation site differ significantly between kinases, indicating differences in sequence selectivity. The unity sequence may be used as a model that will function as a competitive obstacle.
The family of serine/threonine protein kinases is cut up into basophilic, acidophilic, glycine, protein kinases, best use peptide and proline-directed kinases. The first group, which holds kinases like cAMP-dependent protein kinase PKA, protein kinase B/Akt PKB, and protein kinase C PKC, has a liking for positively charged residues in the recognition motif. Acidophilic group kinase consensus sequences, such as casein kinase1/2, contain acidic residues close to the phosphorylation site.
The most numerous family is the proline-directed kinases Mitogen-activated protein kinase MAPK’s, cyclin-dependent. Protein kinases CDK, glycogen synthase kinase-3 GSK-3, and the recognition motifs of these kinases all contain proline. Peptides that are mimics of these recognition sequences can act as substrate competitive inhibitors. For instance, the natural PKA has an RRNAL motif that is similar to the Synthetic short based on the PKI sequence are potent inhibitors.
Self Docking Motifs
Certain peptide inhibitors mimic motifs within the kinase itself. These peptides do not bind to the kinase directly instead, they compete with the kinase for binding to their targets. Three-dimensional structures of some protein kinases have exposed specific regions that bind upstream or downstream partners. Fulani et al. described the activation loop covering the DFG-APE motif present in all protein kinases as a probable template for inhibition.
In MAPK, the activation loop is phosphorylated at the TEY motif by the upstream kinase MEK. Phosphorylation induces a conformational rearrangement of the activation loop. This rearrangement is induced by the matching phosphorylated peptide kinase. Surprisingly, this failed to inhibit MEK, but inhibition was achieved by the non-phosphorylated against MEK activation of MAPK supposedly by competing against MEK. It is apparent from these studies that the induced changes in structure by phosphorylation are significant components for recognition.
In the case at hand, the non-phosphorylated replicated the interaction between MEK and its substrate MAPK. A novel technology called Kin Ace recognized conserved motifs shared by all protein kinases as likely templates for the generation of peptide inhibitors, peptide vitamin c, protein identification, proteomics, epithalon.
Crystal structures of kinases bound to peptide substrates localized in two areas called D and HJ-G positioned at subdomains V and X, respectively, which are responsible for substrate interaction. This observation is used by the Kin Ace technology as a general recipe for sequence peptide inhibitors based on kinases. Peptides corresponding to these areas should inhibit substrate binding, but the diversity of amino acid compositions within these areas implies that specificity can be attained.
COMPUTATIONAL STRUCTURE-BASED DRUG DESIGN
With the increasing amount of peptide protein kinase sequences and three-dimensional structures, there is a valuable starting point for bioinformatic studies like the detection of targeting motifs and distinct docking sites, succeeded by the design and screening of potential peptide inhibitors. The prediction of the interaction geometry between proteins and peptides is a challenging endeavor because of the great flexibility of the ligand. However, successful interface design experiments have been reported, which optimized and enhanced the specificity of proteininterfaces.
Peptide binding to protein kinases is further complicated by the conformational changes many kinases experience when the ligand is bound, including domain motion and local P-loop, C helix, and activation loop alterations. The computational analysis by Helms and McCammon showed that binding of the inhibitory PKI peptide 5-24 to the cAMP-dependent protein kinase stabilizes a closed active conformation of the kinase, while, in the absence, the open state or an intermediate ATP bound state are preferred.
Conclusion
Selective inhibition of peptide protein kinases is a very difficult objective of most drug discovery programs. In this work, we emphasized the chief strategies for the construction of peptide inhibitors of protein kinases and imply that peptides possess many advantages compared to other kinds of drugs like simplicity of discovery, specificity, and safety. In the past, have been regarded as less preferable than small molecule drugs, owing to several limitations.
These include metabolic instability, inability to easily cross cell membranes, possible immunogenicity, and inability to be given orally. Several new approaches, however, were demonstrated to enhance the stability and bioavailability. Chemical modification may make more stable against an enzymatic assault and other formulation methods may be employed to shield the from proteasomal degradation. Formulations considered are liposomes and nanoparticles, microparticles and matrix tablets containing different auxiliary agents like enzyme inhibitors and multifunctional polymers.
The above-described studies were targeted to clarify the interaction energies and/or interaction geometries of peptides to the regulatory domains or catalytic domains of protein kinases. These facts may be applied to identify particular protein peptide interactions, which can, in turn, be employed to design specific peptide or peptide-mimicking inhibitors. Another approach by computational techniques to clarify the inhibitors is the designing of peptides to bind with the kinase substrates or with other modulators of their activities.
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