PDBsum entry 5t5t

Transferase

PDB id: 5t5t

Contents

Protein chains

369 a.a.

163 a.a.

293 a.a.

Ligands

STU

SO4 ×2

75O

AMP ×2

ADP

Metals

_CL ×3

PDB id:

5t5t

Name:

Transferase

Title:

Ampk bound to allosteric activator

Structure:

5'-amp-activated protein kinase catalytic subunit alpha-1. Chain: a. Synonym: ampk subunit alpha-1,acetyl-coa carboxylase kinase,acaca kinase,hydroxymethylglutaryl-coa reductase kinase,hmgcr kinase,tau- protein kinase prkaa1. Ec: 2.7.11.1,2.7.11.27,2.7.11.31,2.7.11.26. Engineered: yes. 5'-amp-activated protein kinase subunit beta-1. Chain: b.

Source:

Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: prkaa1, ampk1. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: prkab1. Gene: prkag1. Expression_system_taxid: 562

Resolution:

3.46Å R-factor: 0.212 R-free: 0.231

Authors:

M.F.Calabrese,R.G.Kurumbail

Key ref:

C.T.Salatto et al. (2017). Selective Activation of AMPK β1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy. J Pharmacol Exp Ther, 361, 303-311. PubMed id: 28289077 DOI: 10.1124/jpet.116.237925

Date:

31-Aug-16 Release date: 29-Mar-17

Protein chain

P54645  (AAPK1_RAT) -  5'-AMP-activated protein kinase catalytic subunit alpha-1 from Rattus norvegicus

Seq: 559 a.a.

Struc: 369 a.a.*

Protein chain

P80386  (AAKB1_RAT) -  5'-AMP-activated protein kinase subunit beta-1 from Rattus norvegicus

Seq: 270 a.a.

Struc: 163 a.a.*

Protein chain

P80385  (AAKG1_RAT) -  5'-AMP-activated protein kinase subunit gamma-1 from Rattus norvegicus

Seq: 330 a.a.

Struc: 293 a.a.

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chain A: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = ADP) corresponds exactly) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = ADP) corresponds exactly) + ADP + H(+)

• Enzyme class 2: Chain A: E.C.2.7.11.26 - [tau protein] kinase.
• Reaction:
  1. L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H⁺
  2. L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H⁺

L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] (Bound ligand (Het Group name = ADP) corresponds exactly) + ADP + H(+)

L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] (Bound ligand (Het Group name = ADP) corresponds exactly) + ADP + H(+)

• Enzyme class 3: Chain A: E.C.2.7.11.31 - [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase.
• Reaction: L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] + ATP = O-phospho-L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] + ADP + H⁺

L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] + ATP = O-phospho-L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] (Bound ligand (Het Group name = ADP) corresponds exactly) + ADP + H(+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1124/jpet.116.237925

J Pharmacol Exp Ther 361:303-311 (2017)

PubMed id: 28289077

Selective Activation of AMPK β1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy.

C.T.Salatto, R.A.Miller, K.O.Cameron, E.Cokorinos, A.Reyes, J.Ward, M.F.Calabrese, R.G.Kurumbail, F.Rajamohan, A.S.Kalgutkar, D.A.Tess, A.Shavnya, N.E.Genung, D.J.Edmonds, A.Jatkar, B.S.Maciejewski, M.Amaro, H.Gandhok, M.Monetti, K.Cialdea, E.Bollinger, J.M.Kreeger, T.M.Coskran, A.C.Opsahl, G.G.Boucher, M.J.Birnbaum, P.DaSilva-Jardine, T.Rolph.

ABSTRACT

Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the β1 subunit. After confirming that human and rodent kidney predominately express AMPK β1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.