3aqv

From Proteopedia

(Difference between revisions)

Revision as of 12:24, 29 July 2020

Human AMP-activated protein kinase alpha 2 subunit kinase domain (T172D) complexed with compound C

Structural highlights

3aqv is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	2yza, 2h6d
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[AAPK2_HUMAN] Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12]

Publication Abstract from PubMed

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK alpha2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK alpha2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal. Like the wild-type apo form, the T172D mutant apo form adopts the autoinhibited structure of the `DFG-out' conformation, with the Phe residue of the DFG motif anchored within the putative ATP-binding pocket. Compound C binding dramatically alters the conformation of the activation loop, which adopts an intermediate conformation between DFG-out and DFG-in. This induced fit forms a compound-C binding pocket composed of the N-lobe, the C-lobe and the hinge of the kinase domain. The pocket partially overlaps with the putative ATP-binding pocket. These three-dimensional structures will be useful to guide drug discovery.

Structural basis for compound C inhibition of the human AMP-activated protein kinase alpha2 subunit kinase domain.,Handa N, Takagi T, Saijo S, Kishishita S, Takaya D, Toyama M, Terada T, Shirouzu M, Suzuki A, Lee S, Yamauchi T, Okada-Iwabu M, Iwabu M, Kadowaki T, Minokoshi Y, Yokoyama S Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):480-7. Epub 2011 Apr 14. PMID:21543851^[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Aguan K, Scott J, See CG, Sarkar NH. Characterization and chromosomal localization of the human homologue of a rat AMP-activated protein kinase-encoding gene: a major regulator of lipid metabolism in mammals. Gene. 1994 Nov 18;149(2):345-50. PMID:7959015
↑ Imamura K, Ogura T, Kishimoto A, Kaminishi M, Esumi H. Cell cycle regulation via p53 phosphorylation by a 5'-AMP activated protein kinase activator, 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem Biophys Res Commun. 2001 Sep 21;287(2):562-7. PMID:11554766 doi:10.1006/bbrc.2001.5627
↑ Yang W, Hong YH, Shen XQ, Frankowski C, Camp HS, Leff T. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J Biol Chem. 2001 Oct 19;276(42):38341-4. Epub 2001 Aug 22. PMID:11518699 doi:10.1074/jbc.C100316200
↑ Hallows KR, Kobinger GP, Wilson JM, Witters LA, Foskett JK. Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells. Am J Physiol Cell Physiol. 2003 May;284(5):C1297-308. Epub 2003 Jan 2. PMID:12519745 doi:10.1152/ajpcell.00227.2002
↑ Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003 Nov 26;115(5):577-90. PMID:14651849
↑ Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005 Apr 29;18(3):283-93. PMID:15866171 doi:10.1016/j.molcel.2005.03.027
↑ Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem. 2007 Oct 12;282(41):30107-19. Epub 2007 Aug 20. PMID:17711846 doi:10.1074/jbc.M705325200
↑ Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, Lee SH, Shong M, Kim JM, Kim J, Chung J. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature. 2007 Jun 21;447(7147):1017-20. Epub 2007 May 7. PMID:17486097 doi:10.1038/nature05828
↑ McGee SL, van Denderen BJ, Howlett KF, Mollica J, Schertzer JD, Kemp BE, Hargreaves M. AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes. 2008 Apr;57(4):860-7. doi: 10.2337/db07-0843. Epub 2008 Jan 9. PMID:18184930 doi:10.2337/db07-0843
↑ McDonald A, Fogarty S, Leclerc I, Hill EV, Hardie DG, Rutter GA. Cell-wide analysis of secretory granule dynamics in three dimensions in living pancreatic beta-cells: evidence against a role for AMPK-dependent phosphorylation of KLC1 at Ser517/Ser520 in glucose-stimulated insulin granule movement. Biochem Soc Trans. 2010 Feb;38(Pt 1):205-8. doi: 10.1042/BST0380205. PMID:20074060 doi:10.1042/BST0380205
↑ Alexander A, Cai SL, Kim J, Nanez A, Sahin M, MacLean KH, Inoki K, Guan KL, Shen J, Person MD, Kusewitt D, Mills GB, Kastan MB, Walker CL. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4153-8. doi: 10.1073/pnas.0913860107., Epub 2010 Feb 16. PMID:20160076 doi:10.1073/pnas.0913860107
↑ Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011 Jan 28;331(6016):456-61. doi: 10.1126/science.1196371. Epub 2010, Dec 23. PMID:21205641 doi:10.1126/science.1196371
↑ Handa N, Takagi T, Saijo S, Kishishita S, Takaya D, Toyama M, Terada T, Shirouzu M, Suzuki A, Lee S, Yamauchi T, Okada-Iwabu M, Iwabu M, Kadowaki T, Minokoshi Y, Yokoyama S. Structural basis for compound C inhibition of the human AMP-activated protein kinase alpha2 subunit kinase domain. Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):480-7. Epub 2011 Apr 14. PMID:21543851 doi:10.1107/S0907444911010201

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3aqv"

@@ Line 1: / Line 1: @@
 ==Human AMP-activated protein kinase alpha 2 subunit kinase domain (T172D) complexed with compound C==
-<StructureSection load='3aqv' size='340' side='right' caption='[[3aqv]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
+<StructureSection load='3aqv' size='340' side='right'caption='[[3aqv]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3aqv]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AQV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3AQV FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3aqv]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AQV OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3AQV FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=TAK:6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE'>TAK</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TAK:6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE'>TAK</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2yza|2yza]], [[2h6d|2h6d]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3aqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3aqv OCA], [http://pdbe.org/3aqv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3aqv RCSB], [http://www.ebi.ac.uk/pdbsum/3aqv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3aqv ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3aqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3aqv OCA], [http://pdbe.org/3aqv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3aqv RCSB], [http://www.ebi.ac.uk/pdbsum/3aqv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3aqv ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 22: @@
 ==See Also==
-*[[AMP-activated protein kinase|AMP-activated protein kinase]]
+*[[AMP-activated protein kinase 3D structures|AMP-activated protein kinase 3D structures]]
 == References ==
 <references/>
@@ Line 28: / Line 28: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Handa, N]]

3aqv

From Proteopedia

Revision as of 12:24, 29 July 2020

Human AMP-activated protein kinase alpha 2 subunit kinase domain (T172D) complexed with compound C

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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