6UNC

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

6UNC の概要

• エントリーDOI: 10.2210/pdb6unc/pdb
• 分子名称: Metallophos domain-containing protein, MANGANESE (II) ION, FE (III) ION, ... (4 entities in total)
• 機能のキーワード: phosphopantetheinyl hydrolase, structural genomics, psi-2, protein structure initiative, tb structural genomics consortium, tbsgc, hydrolase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 145959.30

構造登録者

Mosior, J.W.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (登録日: 2019-10-11, 公開日: 2020-04-22, 最終更新日: 2024-11-06)

主引用文献

Mosior, J.,Bourland, R.,Soma, S.,Nathan, C.,Sacchettini, J.
Structural insights into phosphopantetheinyl hydrolase PptH from Mycobacterium tuberculosis.
Protein Sci., 29:744-757, 2020

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.

PubMed: 31886928
DOI: 10.1002/pro.3813

実験手法

X-RAY DIFFRACTION (2.5 Å)