6UNC

The crystal structure of Phosphopantetheinyl Hydrolase (PptH) from Mycobacterium tuberculosis

PDB DOI: https://doi.org/10.2210/pdb6UNC/pdb

Classification: HYDROLASE
Organism(s): Mycobacterium tuberculosis H37Rv
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2019-10-11 Released: 2020-04-22
Deposition Author(s): Mosior, J.W., Sacchettini, J.C., TB Structural Genomics Consortium (TBSGC)
Funding Organization(s): National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI), Welch Foundation

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.50 Å
R-Value Free: 0.222
R-Value Work: 0.186
R-Value Observed: 0.188

wwPDB Validation 3D Report Full Report

This is version 1.0 of the entry. See complete history.

Literature

Structural insights into phosphopantetheinyl hydrolase PptH from Mycobacterium tuberculosis.

Mosior, J., Bourland, R., Soma, S., Nathan, C., Sacchettini, J.

(2020) Protein Sci 29: 744-757

PubMed: 31886928 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/pro.3813
Primary Citation of Related Structures:
6UNC

PubMed Abstract:
The amidinourea 8918 was recently reported to inhibit the type II phosphopantetheinyl transferase (PPTase) of Mycobacterium tuberculosis (Mtb), PptT, a potential drug-target that activates synthases and synthetases involved in cell wall biosynthesis and secondary metabolism. Surprisingly, high-level resistance to 8918 occurred in Mtb harboring mutations within the gene adjacent to pptT, rv2795c, highlighting the role of the encoded protein as a potentiator of the bactericidal action of the amidinourea. Those studies revealed that Rv2795c (PptH) is a phosphopantetheinyl (PpT) hydrolase, possessing activity antagonistic with respect to PptT. We have solved the crystal structure of Mtb's phosphopantetheinyl hydrolase, making it the first phosphopantetheinyl (carrier protein) hydrolase structurally characterized. The 2.5 Å structure revealed the hydrolases' four-layer (α/β/β/α) sandwich fold featuring a Mn-Fe binuclear center within the active site. A structural similarity search confirmed that PptH most closely resembles previously characterized metallophosphoesterases (MPEs), particularly within the vicinity of the active site, suggesting that it may utilize a similar catalytic mechanism. In addition, analysis of the structure has allowed for the rationalization of the previously reported PptH mutations associated with 8918-resistance. Notably, differences in the sequences and predicted structural characteristics of the PpT hydrolases PptH of Mtb and E. coli's acyl carrier protein hydrolase (AcpH) indicate that the two enzymes evolved convergently and therefore are representative of two distinct PpT hydrolase families.

Organizational Affiliation

Department of Biochemistry and Biophysics, Texas Agricultural and Mechanical University, College Station, Texas.

Macromolecule Content

Total Structure Weight: 145.96 kDa
Atom Count: 9,287
Modelled Residue Count: 1,118
Deposited Residue Count: 1,252
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Metallophos domain-containing protein	A, B, C, D	313	Mycobacterium tuberculosis H37Rv	Mutation(s): 0 Gene Names: Rv2795c
UniProt
Find proteins for I6YEE1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)) Explore I6YEE1 Go to UniProtKB: I6YEE1
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	I6YEE1
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
FE (Subject of Investigation/LOI) Query on FE Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain H [auth B] SDF format, chain J [auth C] SDF format, chain L [auth D] MOL2 format, chain F [auth A] MOL2 format, chain H [auth B] MOL2 format, chain J [auth C] MOL2 format, chain L [auth D]	F [auth A], H [auth B], J [auth C], L [auth D]	FE (III) ION Fe VTLYFUHAOXGGBS-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D] Interactions & Density Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D]
MN (Subject of Investigation/LOI) Query on MN Download Ideal Coordinates CCD File SDF format, chain G [auth B] SDF format, chain I [auth C] SDF format, chain K [auth D] SDF format, chain E [auth A] MOL2 format, chain G [auth B] MOL2 format, chain I [auth C] MOL2 format, chain K [auth D] MOL2 format, chain E [auth A]	E [auth A], G [auth B], I [auth C], K [auth D]	MANGANESE (II) ION Mn WAEMQWOKJMHJLA-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D] Interactions & Density Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D]