5YHT

Crystal structure of a phosphatase from Mycobacterium tuberculosis in complex with its substrate

Summary for 5YHT

• Entry DOI: 10.2210/pdb5yht/pdb
• Related: 5YFL
• Descriptor: Histidinol-phosphatase, ZINC ION, PHOSPHORIC ACID MONO-[2-AMINO-3-(3H-IMIDAZOL-4-YL)-PROPYL]ESTER, ... (6 entities in total)
• Functional Keywords: mycobacterium tuberculosis, phosphatase, histidinol, enzyme activity, hydrolase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 58214.20

Authors

Biswal, B.K.,Jha, B. (deposition date: 2017-09-29, release date: 2018-05-23, Last modification date: 2023-11-22)

Primary citation

Jha, B.,Kumar, D.,Sharma, A.,Dwivedy, A.,Singh, R.,Biswal, B.K.
Identification and structural characterization of a histidinol phosphate phosphatase fromMycobacterium tuberculosis
J. Biol. Chem., 293:10102-10118, 2018

PubMed Abstract: The absence of a histidine biosynthesis pathway in humans, coupled with histidine essentiality for survival of the important human pathogen (), underscores the importance of the bacterial enzymes of this pathway as major antituberculosis drug targets. However, the identity of the mycobacterial enzyme that functions as the histidinol phosphate phosphatase (HolPase) of this pathway remains to be established. Here, we demonstrate that the enzyme encoded by the gene, belonging to the inositol monophosphatase (IMPase) family, functions as the HolPase and specifically dephosphorylates histidinol phosphate. The crystal structure of Rv3137 in apo form enabled us to dissect its distinct structural features. Furthermore, the holo-complex structure revealed that a unique cocatalytic multizinc-assisted mode of substrate binding and catalysis is the hallmark of HolPase. Interestingly, the enzyme-substrate complex structure unveiled that although monomers possess individual catalytic sites they share a common product-exit channel at the dimer interface. Furthermore, target-based screening against HolPase identified several small-molecule inhibitors of this enzyme. Taken together, our study unravels the missing enzyme link in the histidine biosynthesis pathway, augments our current mechanistic understanding of histidine production in , and has helped identify potential inhibitors of this bacterial pathway.

PubMed: 29752410
DOI: 10.1074/jbc.RA118.002299

Experimental method

X-RAY DIFFRACTION (2.87 Å)