PDBsum entry 4s1b

Hydrolase

PDB id: 4s1b

Contents

Protein chains

213 a.a.

Ligands

2BA ×2

Metals

_FE ×4

Waters ×215

PDB id:

4s1b

Name:

Hydrolase

Title:

Crystal structure of l. Monocytogenes phosphodiesterase pgph hd domain in complex with cyclic-di-amp

Structure:

Lmo1466 protein. Chain: a, d. Engineered: yes

Source:

Listeria monocytogenes. Organism_taxid: 169963. Strain: atcc baa-679 / egd-e. Gene: lmo1466, pgph. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.165 R-free: 0.202

Authors:

S.Luo,L.Tong

Key ref:

T.N.Huynh et al. (2015). An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence. Proc Natl Acad Sci U S A, 112, E747. PubMed id: 25583510 DOI: 10.1073/pnas.1416485112

Date:

12-Jan-15 Release date: 11-Feb-15

Protein chains

Q8Y746  (Q8Y746_LISMO) -  Lmo1466 protein from Listeria monocytogenes serovar 1/2a (strain ATCC BAA-679 / EGD-e)

Seq: 718 a.a.

Struc: 213 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1073/pnas.1416485112

Proc Natl Acad Sci U S A 112:E747 (2015)

PubMed id: 25583510

An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence.

T.N.Huynh, S.Luo, D.Pensinger, J.D.Sauer, L.Tong, J.J.Woodward.

ABSTRACT

The nucleotide cyclic di-3',5'- adenosine monophosphate (c-di-AMP) was recently identified as an essential and widespread second messenger in bacterial signaling. Among c-di-AMP-producing bacteria, altered nucleotide levels result in several physiological defects and attenuated virulence. Thus, a detailed molecular understanding of c-di-AMP metabolism is of both fundamental and practical interest. Currently, c-di-AMP degradation is recognized solely among DHH-DHHA1 domain-containing phosphodiesterases. Using chemical proteomics, we identified the Listeria monocytogenes protein PgpH as a molecular target of c-di-AMP. Biochemical and structural studies revealed that the PgpH His-Asp (HD) domain bound c-di-AMP with high affinity and specifically hydrolyzed this nucleotide to 5'-pApA. PgpH hydrolysis activity was inhibited by ppGpp, indicating a cross-talk between c-di-AMP signaling and the stringent response. Genetic analyses supported coordinated regulation of c-di-AMP levels in and out of the host. Intriguingly, a L. monocytogenes mutant that lacks c-di-AMP phosphodiesterases exhibited elevated c-di-AMP levels, hyperinduced a host type-I IFN response, and was significantly attenuated for infection. Furthermore, PgpH homologs, which belong to the 7TMR-HD family, are widespread among hundreds of c-di-AMP synthesizing microorganisms. Thus, PgpH represents a broadly conserved class of c-di-AMP phosphodiesterase with possibly other physiological functions in this crucial signaling network.