NDLI: Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation

Content Provider	Royal Society of Chemistry (RSC)
Author	Nam, Kwangho Li, Yaozong
Copyright Year	2017
Abstract	Despite the importance of kinases' catalytic activity regulation in cell signaling, detailed mechanisms underlying their activity regulation are poorly understood. Herein, using insulin-like growth factor 1 receptor kinase (IGF-1RK) as a model, the mechanisms of kinase regulation by its activation loop (A-loop) phosphorylation were investigated through molecular dynamics (MD) and alchemical free energy simulations. Analyses of the simulation results and free energy landscapes determined for the entire catalytic cycle of the kinase revealed that A-loop phosphorylation affects each step in the IGF-1RK catalytic cycle, including conformational change, substrate binding/product release and catalytic phosphoryl transfer. Specifically, the conformational equilibrium of the kinase is shifted by 13.2 kcal mol−1 to favor the active conformation after A-loop phosphorylation, which increases substrate binding affinity of the activated kinase. This free energy shift is achieved primarily via destabilization of the inactive conformation. The free energy of the catalytic reaction is also changed by 3.3 kcal mol−1 after the phosphorylation and in the end, facilitates product release. Analyses of MD simulations showed that A-loop phosphorylation produces these energetic effects by perturbing the side chain interactions around each A-loop tyrosine. These interaction changes are propagated to the remainder of the kinase to modify the orientations and dynamics of the αC-helix and A-loop, and together yield the observed free energy changes. Since many protein kinases share similar interactions identified in this work, the mechanisms of kinase allostery and catalysis unraveled here can be applicable to them.
Starting Page	3453
Ending Page	3464
Page Count	12
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	8
Issue Number	5
Journal	Chemical Science
DOI	10.1039/c7sc00055c
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Tyrosine Signal transduction Phosphorylation Cell surface receptor Kinase Intrinsically disordered proteins Molecular dynamics Conformational change Protein Growth factor Minuscule 2814 Catalytic cycle
Content Type	Text
Resource Type	Article
Subject	Chemistry

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

The bps domain of grb10 inhibits the catalytic activity of the insulin and igf1 receptors (2001).

Polyubiquitination of Insulin-like Growth Factor I Receptor (IGF-IR) Activation Loop Promotes Antibody-induced Receptor Internalization and Down-regulation

Structural Determinants of the Insulin Receptor-related Receptor Activation by Alkali

The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway

Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes

050 Tannic Acid, a Potent Inhibitor of Epidermal Growth Factor (2005)

Novel signal transduction pathway for luteinizing hormone and its interaction with insulin: activation of janus kinase/signal transducer and activator of transcription and phosphoinositol 3-kinase/akt pathways.

Angiotensin II activation of insulin-like growth factor 1 receptor transcription is mediated by a tyrosine kinase-dependent redox-sensitive mechanism.

Differential modulation of the tyrosine phosphorylation state of the insulin receptor by irs (insulin receptor subunit) proteins (1999).

Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation

Similar Documents

The bps domain of grb10 inhibits the catalytic activity of the insulin and igf1 receptors (2001).

Polyubiquitination of Insulin-like Growth Factor I Receptor (IGF-IR) Activation Loop Promotes Antibody-induced Receptor Internalization and Down-regulation

Structural Determinants of the Insulin Receptor-related Receptor Activation by Alkali

The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway

Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes

050 Tannic Acid, a Potent Inhibitor of Epidermal Growth Factor (2005)

Novel signal transduction pathway for luteinizing hormone and its interaction with insulin: activation of janus kinase/signal transducer and activator of transcription and phosphoinositol 3-kinase/akt pathways.

Angiotensin II activation of insulin-like growth factor 1 receptor transcription is mediated by a tyrosine kinase-dependent redox-sensitive mechanism.

Differential modulation of the tyrosine phosphorylation state of the insulin receptor by irs (insulin receptor subunit) proteins (1999).

Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation