Limits...
Simulation of different truncated p16(INK4a) forms and in silico study of interaction with Cdk4.

Fahham N, Ghahremani MH, Sardari S, Vaziri B, Ostad SN - Cancer Inform (2008)

Bottom Line: Considering shape and shape/electrostatic total energy, structures containing ANK II, III and IV motifs that lack the N-terminal region of the full length p16 molecule showed the best fit complexes among the p16 truncated forms.The free energies were compatible with that of p16 full length original form, the full length.It seems that the N-terminal of the molecule is not crucial for the interaction since the truncated structure containing only this region did not show a good total energy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute, Tehran, Iran.

ABSTRACT
Protein-protein interactions studies can greatly increase the amount of structural and functional information pertaining to biologically active molecules and processes. The information obtained from such studies can lead to design and application of new modification in order to obtain a desired bioactivity. Many application packages and servers performing docking, such as HEX, DOT, AUTODOCK, and ZDOCK are now available for predicting the lowest free energy state of a protein complex. In this study, we have focused on cyclin-dependent kinase 4 (Cdk4), a key molecule in the regulation of cell cycle progression at the G(1)-S phase restriction point and p16(INK4a), a tumor suppressor which inhibits Cdk4 activity. Truncated structures were created to find the more critical regions of p16 for interaction. The tertiary structures were determined by ProSAL, GENO3D Web Server. We evaluated their interactions with Cdk4 using two docking systems, HEX 4.5 and DOT 1. Calculations were performed on a high-speed computer. Minimizations and visualizations were carried out by PdbViewer 3.7. Considering shape and shape/electrostatic total energy, structures containing ANK II, III and IV motifs that lack the N-terminal region of the full length p16 molecule showed the best fit complexes among the p16 truncated forms. The free energies were compatible with that of p16 full length original form, the full length. It seems that the N-terminal of the molecule is not crucial for the interaction since the truncated structure containing only this region did not show a good total energy.

No MeSH data available.


Related in: MedlinePlus

Representation of complex molecules docked by HEX. a) p16 binds to both the N and C-terminal lobes of Cdk4, predominantly the N-terminal lobe. b) truncated structure H interacts with Cdk4 in almost the same manner as the full length molecule.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC2664699&req=5

f6-cin-07-01: Representation of complex molecules docked by HEX. a) p16 binds to both the N and C-terminal lobes of Cdk4, predominantly the N-terminal lobe. b) truncated structure H interacts with Cdk4 in almost the same manner as the full length molecule.

Mentions: The ankyrin motifs possess highest primary sequence conservation in the ankyrin motifs and mutations in these regions seem to disrupt the function of the protein. While few natural mutations can be detected in the flexible N- and C-terminal segments, in most of the mutants, at least one change in the conserved ankyrin sequence has occurred. It was shown that point mutations in the conserved ankyrin sequence affected the activity, and mutation in other regions had no apparent effect. (Byeon et al. 1998; Yuan et al. 1999; Yang et al. 1996). The comparison between total free energy of structure H and F may demonstrate that ankyrin repeats III and IV with intervening loops 2 and 3 can cover for Cdk4 interaction and ankyrin IV motif may play somewhat a helper role in the interaction since its removal has weakened the obtained free energy of binding and also changed the binding site on Cdk4 in structure A. It is previously showed that the deletion of the fourth ankyrin repeat abolished the activity completely (Yang et al. 1995). Figure 6 presents the complex of p16-Cdk4 and truncated structure H-Cdk4, as a sample with good interaction profile, after being docked with Hex.


Simulation of different truncated p16(INK4a) forms and in silico study of interaction with Cdk4.

Fahham N, Ghahremani MH, Sardari S, Vaziri B, Ostad SN - Cancer Inform (2008)

Representation of complex molecules docked by HEX. a) p16 binds to both the N and C-terminal lobes of Cdk4, predominantly the N-terminal lobe. b) truncated structure H interacts with Cdk4 in almost the same manner as the full length molecule.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2664699&req=5

f6-cin-07-01: Representation of complex molecules docked by HEX. a) p16 binds to both the N and C-terminal lobes of Cdk4, predominantly the N-terminal lobe. b) truncated structure H interacts with Cdk4 in almost the same manner as the full length molecule.
Mentions: The ankyrin motifs possess highest primary sequence conservation in the ankyrin motifs and mutations in these regions seem to disrupt the function of the protein. While few natural mutations can be detected in the flexible N- and C-terminal segments, in most of the mutants, at least one change in the conserved ankyrin sequence has occurred. It was shown that point mutations in the conserved ankyrin sequence affected the activity, and mutation in other regions had no apparent effect. (Byeon et al. 1998; Yuan et al. 1999; Yang et al. 1996). The comparison between total free energy of structure H and F may demonstrate that ankyrin repeats III and IV with intervening loops 2 and 3 can cover for Cdk4 interaction and ankyrin IV motif may play somewhat a helper role in the interaction since its removal has weakened the obtained free energy of binding and also changed the binding site on Cdk4 in structure A. It is previously showed that the deletion of the fourth ankyrin repeat abolished the activity completely (Yang et al. 1995). Figure 6 presents the complex of p16-Cdk4 and truncated structure H-Cdk4, as a sample with good interaction profile, after being docked with Hex.

Bottom Line: Considering shape and shape/electrostatic total energy, structures containing ANK II, III and IV motifs that lack the N-terminal region of the full length p16 molecule showed the best fit complexes among the p16 truncated forms.The free energies were compatible with that of p16 full length original form, the full length.It seems that the N-terminal of the molecule is not crucial for the interaction since the truncated structure containing only this region did not show a good total energy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute, Tehran, Iran.

ABSTRACT
Protein-protein interactions studies can greatly increase the amount of structural and functional information pertaining to biologically active molecules and processes. The information obtained from such studies can lead to design and application of new modification in order to obtain a desired bioactivity. Many application packages and servers performing docking, such as HEX, DOT, AUTODOCK, and ZDOCK are now available for predicting the lowest free energy state of a protein complex. In this study, we have focused on cyclin-dependent kinase 4 (Cdk4), a key molecule in the regulation of cell cycle progression at the G(1)-S phase restriction point and p16(INK4a), a tumor suppressor which inhibits Cdk4 activity. Truncated structures were created to find the more critical regions of p16 for interaction. The tertiary structures were determined by ProSAL, GENO3D Web Server. We evaluated their interactions with Cdk4 using two docking systems, HEX 4.5 and DOT 1. Calculations were performed on a high-speed computer. Minimizations and visualizations were carried out by PdbViewer 3.7. Considering shape and shape/electrostatic total energy, structures containing ANK II, III and IV motifs that lack the N-terminal region of the full length p16 molecule showed the best fit complexes among the p16 truncated forms. The free energies were compatible with that of p16 full length original form, the full length. It seems that the N-terminal of the molecule is not crucial for the interaction since the truncated structure containing only this region did not show a good total energy.

No MeSH data available.


Related in: MedlinePlus