6P5O
The structure of rat cytosolic PEPCK in complex with 3-(carboxymethylthiol)-picolinic acid
Summary for 6P5O
| Entry DOI | 10.2210/pdb6p5o/pdb |
| Descriptor | Phosphoenolpyruvate carboxykinase, cytosolic [GTP], MANGANESE (II) ION, 3-[(carboxymethyl)sulfanyl]pyridine-2-carboxylic acid, ... (5 entities in total) |
| Functional Keywords | kinase, gluconeogenesis, lyase, lyase-inhibitor complex, lyase/inhibitor |
| Biological source | Rattus norvegicus (Rat) |
| Total number of polymer chains | 1 |
| Total formula weight | 69845.74 |
| Authors | Mcleod, M.J.,Holyoak, T. (deposition date: 2019-05-30, release date: 2019-09-18, Last modification date: 2023-10-11) |
| Primary citation | Mcleod, M.J.,Krismanich, A.P.,Assoud, A.,Dmitrienko, G.I.,Holyoak, T. Characterization of 3-[(Carboxymethyl)thio]picolinic Acid: A Novel Inhibitor of Phosphoenolpyruvate Carboxykinase. Biochemistry, 58:3918-3926, 2019 Cited by PubMed Abstract: Phosphoenolpyruvate carboxykinase (PEPCK) has traditionally been characterized for its role in the first committed step of gluconeogenesis. The current understanding of PEPCK's metabolic role has recently expanded to include it serving as a general mediator of tricarboxylic acid cycle flux. Selective inhibition of PEPCK and has been achieved with 3-mercaptopicolinic acid (MPA) ( ∼ 8 μM), whose mechanism of inhibition has been elucidated only recently. On the basis of crystallographic and mechanistic data of various inhibitors of PEPCK, MPA was used as the initial chemical scaffold to create a potentially more selective inhibitor, 3-[(carboxymethyl)thio]picolinic acid (CMP), which has been characterized both structurally and kinetically here. These data demonstrate that CMP acts as a competitive inhibitor at the OAA/PEP binding site, with its picolinic acid moiety coordinating directly with the M1 metal in the active site ( ∼ 29-55 μM). The extended carboxy tail occupies a secondary binding cleft that was previously shown could be occupied by sulfoacetate ( ∼ 82 μM) and for the first time demonstrates the simultaneous occupation of both OAA/PEP subsites by a single molecular structure. By occupying both the OAA/PEP binding subsites simultaneously, CMP and similar molecules can potentially be used as a starting point for the creation of additional selective inhibitors of PEPCK. PubMed: 31461616DOI: 10.1021/acs.biochem.9b00583 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.49 Å) |
Structure validation
Download full validation report
