PDBsum entry 4cfe

Transferase

PDB id: 4cfe

Contents

Protein chains

426 a.a.

168 a.a.

404 a.a.

294 a.a.

Ligands

STU ×2

992 ×2

AMP ×6

Waters ×31

PDB id:

4cfe

Name:

Transferase

Title:

Structure of full length human ampk in complex with a small molecule activator, a benzimidazole derivative (991)

Structure:

5'-amp-activated protein kinase catalytic subunit alpha-2. Chain: a, c. Synonym: ampk subunit alpha-2, acetyl-coa carboxylase kinase, acaca kinase, hydroxymethylglutaryl-coa reductase kinase, hmgcr kinase. Ec: 2.7.11.1, 2.7.11.27, 2.7.11.31. Engineered: yes. Other_details: a 172 thr and c 172 thr are phosphorylated.. 5'-amp-activated protein kinase subunit beta-1. Chain: b, d.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

3.02Å R-factor: 0.219 R-free: 0.253

Authors:

B.Xiao,M.J.Sanders,D.Carmena,N.J.Bright,L.F.Haire,E.Underwood, B.R.Patel,R.B.Heath,P.A.Walker,S.Hallen,F.Giordanetto,S.R.Martin, D.Carling,S.J.Gamblin

Key ref:

B.Xiao et al. (2013). Structural basis of AMPK regulation by small molecule activators. Nat Commun, 4, 3017. PubMed id: 24352254 DOI: 10.1038/ncomms4017

Date:

14-Nov-13 Release date: 25-Dec-13

Protein chain

P54646  (AAPK2_HUMAN) -  5'-AMP-activated protein kinase catalytic subunit alpha-2 from Homo sapiens

Seq: 552 a.a.

Struc: 426 a.a.*

Protein chains

Q9Y478  (AAKB1_HUMAN) -  5'-AMP-activated protein kinase subunit beta-1 from Homo sapiens

Seq: 270 a.a.

Struc: 168 a.a.

Protein chain

P54646  (AAPK2_HUMAN) -  5'-AMP-activated protein kinase catalytic subunit alpha-2 from Homo sapiens

Seq: 552 a.a.

Struc: 404 a.a.*

Protein chains

P54619  (AAKG1_HUMAN) -  5'-AMP-activated protein kinase subunit gamma-1 from Homo sapiens

Seq: 331 a.a.

Struc: 294 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains A, C: 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 = AMP) matches with 85.19% similarity) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = AMP) matches with 85.19% similarity) + ADP + H(+)

• Enzyme class 2: Chains A, C: 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 = AMP) matches with 85.19% similarity) + 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: 10.1038/ncomms4017

Nat Commun 4:3017 (2013)

PubMed id: 24352254

Structural basis of AMPK regulation by small molecule activators.

B.Xiao, M.J.Sanders, D.Carmena, N.J.Bright, L.F.Haire, E.Underwood, B.R.Patel, R.B.Heath, P.A.Walker, S.Hallen, F.Giordanetto, S.R.Martin, D.Carling, S.J.Gamblin.

ABSTRACT

AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders.