4QSK

Crystal Structure of L. monocytogenes Pyruvate Carboxylase in complex with Cyclic-di-AMP

Summary for 4QSK

• Entry DOI: 10.2210/pdb4qsk/pdb
• Related: 4QSH 4QSL
• Descriptor: Pyruvate carboxylase, (2R,3R,3aS,5R,7aR,9R,10R,10aS,12R,14aR)-2,9-bis(6-amino-9H-purin-9-yl)octahydro-2H,7H-difuro[3,2-d:3',2'-j][1,3,7,9,2,8 ]tetraoxadiphosphacyclododecine-3,5,10,12-tetrol 5,12-dioxide, CITRATE ANION, ... (4 entities in total)
• Functional Keywords: tim barrel, pyruvate carboxylase, acetyl-coa, biotin, ligase
• Biological source: Listeria monocytogenes
• Total number of polymer chains: 2
• Total formula weight: 258582.71

Authors

Choi, P.H.,Tong, L. (deposition date: 2014-07-04, release date: 2014-10-29, Last modification date: 2023-09-20)

Primary citation

Sureka, K.,Choi, P.H.,Precit, M.,Delince, M.,Pensinger, D.A.,Huynh, T.N.,Jurado, A.R.,Goo, Y.A.,Sadilek, M.,Iavarone, A.T.,Sauer, J.D.,Tong, L.,Woodward, J.J.
The Cyclic Dinucleotide c-di-AMP Is an Allosteric Regulator of Metabolic Enzyme Function.
Cell(Cambridge,Mass.), 158:1389-1401, 2014

PubMed Abstract: Cyclic di-adenosine monophosphate (c-di-AMP) is a broadly conserved second messenger required for bacterial growth and infection. However, the molecular mechanisms of c-di-AMP signaling are still poorly understood. Using a chemical proteomics screen for c-di-AMP-interacting proteins in the pathogen Listeria monocytogenes, we identified several broadly conserved protein receptors, including the central metabolic enzyme pyruvate carboxylase (LmPC). Biochemical and crystallographic studies of the LmPC-c-di-AMP interaction revealed a previously unrecognized allosteric regulatory site 25 Å from the active site. Mutations in this site disrupted c-di-AMP binding and affected catalytic activity of LmPC as well as PC from pathogenic Enterococcus faecalis. C-di-AMP depletion resulted in altered metabolic activity in L. monocytogenes. Correction of this metabolic imbalance rescued bacterial growth, reduced bacterial lysis, and resulted in enhanced bacterial burdens during infection. These findings greatly expand the c-di-AMP signaling repertoire and reveal a central metabolic regulatory role for a cyclic dinucleotide.

PubMed: 25215494
DOI: 10.1016/j.cell.2014.07.046

Experimental method

X-RAY DIFFRACTION (2.7 Å)