Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations
Protein kinase Iα (PKGIα) is a pivotal cyclic guanosine monophosphate (cGMP) signalling protein. Major steps related to the structural plasticity of PKGIα have been inferred but the structural aspects of the auto-inhibition and multidomain tertiary organization of human PKGIα in active and inactive...
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Elsevier
2020-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037020303056 |
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| author | Arooma Maryam Rana Rehan Khalid Sundeep Chaitanya Vedithi Abdulilah ECE Suleyman Selim Çınaroğlu Abdul Rauf Siddiqi Tom L. Blundell |
| author_facet | Arooma Maryam Rana Rehan Khalid Sundeep Chaitanya Vedithi Abdulilah ECE Suleyman Selim Çınaroğlu Abdul Rauf Siddiqi Tom L. Blundell |
| author_sort | Arooma Maryam |
| collection | DOAJ |
| description | Protein kinase Iα (PKGIα) is a pivotal cyclic guanosine monophosphate (cGMP) signalling protein. Major steps related to the structural plasticity of PKGIα have been inferred but the structural aspects of the auto-inhibition and multidomain tertiary organization of human PKGIα in active and inactive form are not clear. Here we combine computational comparative modelling, protein–protein docking and molecular dynamics (MD) simulations to investigate structural details of the repressed state of the catalytic domain of PKGIα. Exploration of the potential inhibitory conformation of the auto-inhibitory domain (AI) within the catalytic cleft reveals that the pseudo-substrate motif binds with residues of the glycine rich loop and substrate-binding lobe. Dynamic changes as a result of coupling of the catalytic and AI domains are also investigated. The three-dimensional homodimeric models of PKGIα in the active and inactive state indicate that PKGIα in its inactive-state attains a compact globular structure where cyclic nucleotide binding (CNB-A/B) domains are buried, whereas the catalytic domains are inaccessible with their substrate-binding pockets facing the N-terminal of CNB-A. Contrary to this, the active-state model of PKGIα shows an extended conformation where CNB-A/B domains are slightly rearranged and the catalytic domains of homodimer flanking the C-terminal with their substrate binding lobes free to entrap downstream proteins. These findings are consistent with previously reported static images of the multidomain organization of PKGIα. Structural insights pertaining to the conformational heterogeneity and auto-inhibition of PKGIα provided in this study may help to understand the dynamics-driven effective regulation of PKGIα. |
| first_indexed | 2024-12-16T14:42:26Z |
| format | Article |
| id | doaj.art-8e1da6b6ed9d4382b8d4c7287cadec20 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-12-16T14:42:26Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-8e1da6b6ed9d4382b8d4c7287cadec202022-12-21T22:27:52ZengElsevierComputational and Structural Biotechnology Journal2001-03702020-01-011816251638Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulationsArooma Maryam0Rana Rehan Khalid1Sundeep Chaitanya Vedithi2Abdulilah ECE3Suleyman Selim Çınaroğlu4Abdul Rauf Siddiqi5Tom L. Blundell6Department of Biosciences, COMSATS University Islamabad (CUI), Park Road, Islamabad 4550, Pakistan; Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd., Cambridge CB2 1GA, UK; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul 34010, TurkeyDepartment of Biosciences, COMSATS University Islamabad (CUI), Park Road, Islamabad 4550, PakistanDepartment of Biochemistry, University of Cambridge, 80 Tennis Court Rd., Cambridge CB2 1GA, UKDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul 34010, TurkeyDepartment of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UKDepartment of Biosciences, COMSATS University Islamabad (CUI), Park Road, Islamabad 4550, Pakistan; Corresponding authors.Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd., Cambridge CB2 1GA, UK; Corresponding authors.Protein kinase Iα (PKGIα) is a pivotal cyclic guanosine monophosphate (cGMP) signalling protein. Major steps related to the structural plasticity of PKGIα have been inferred but the structural aspects of the auto-inhibition and multidomain tertiary organization of human PKGIα in active and inactive form are not clear. Here we combine computational comparative modelling, protein–protein docking and molecular dynamics (MD) simulations to investigate structural details of the repressed state of the catalytic domain of PKGIα. Exploration of the potential inhibitory conformation of the auto-inhibitory domain (AI) within the catalytic cleft reveals that the pseudo-substrate motif binds with residues of the glycine rich loop and substrate-binding lobe. Dynamic changes as a result of coupling of the catalytic and AI domains are also investigated. The three-dimensional homodimeric models of PKGIα in the active and inactive state indicate that PKGIα in its inactive-state attains a compact globular structure where cyclic nucleotide binding (CNB-A/B) domains are buried, whereas the catalytic domains are inaccessible with their substrate-binding pockets facing the N-terminal of CNB-A. Contrary to this, the active-state model of PKGIα shows an extended conformation where CNB-A/B domains are slightly rearranged and the catalytic domains of homodimer flanking the C-terminal with their substrate binding lobes free to entrap downstream proteins. These findings are consistent with previously reported static images of the multidomain organization of PKGIα. Structural insights pertaining to the conformational heterogeneity and auto-inhibition of PKGIα provided in this study may help to understand the dynamics-driven effective regulation of PKGIα.http://www.sciencedirect.com/science/article/pii/S2001037020303056Cyclic guanosine monophosphate (cGMP)Protein kinase Iα (PKGIα)Auto-inhibitory domain (AI)Cyclic Nucleotide binding domain-A (CNB-A) |
| spellingShingle | Arooma Maryam Rana Rehan Khalid Sundeep Chaitanya Vedithi Abdulilah ECE Suleyman Selim Çınaroğlu Abdul Rauf Siddiqi Tom L. Blundell Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations Computational and Structural Biotechnology Journal Cyclic guanosine monophosphate (cGMP) Protein kinase Iα (PKGIα) Auto-inhibitory domain (AI) Cyclic Nucleotide binding domain-A (CNB-A) |
| title | Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations |
| title_full | Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations |
| title_fullStr | Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations |
| title_full_unstemmed | Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations |
| title_short | Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations |
| title_sort | exploring the structural basis of conformational heterogeneity and autoinhibition of human cgmp specific protein kinase iα through computational modelling and molecular dynamics simulations |
| topic | Cyclic guanosine monophosphate (cGMP) Protein kinase Iα (PKGIα) Auto-inhibitory domain (AI) Cyclic Nucleotide binding domain-A (CNB-A) |
| url | http://www.sciencedirect.com/science/article/pii/S2001037020303056 |
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