6OZ8

Crystal structure of Mtb aspartate decarboxylase in active form

Summary for 6OZ8

• Entry DOI: 10.2210/pdb6oz8/pdb
• Related: 6OYY
• Descriptor: Aspartate 1 decarboxylase beta chain, Aspartate 1 decarboxylase alpha chain (3 entities in total)
• Functional Keywords: structural genomics, tb structural genomics consortium, tbsgc, lyase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 12
• Total formula weight: 95838.71

Authors

Sun, Q.,Li, X.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2019-05-15, release date: 2020-02-05, Last modification date: 2024-10-09)

Primary citation

Sun, Q.,Li, X.,Perez, L.M.,Shi, W.,Zhang, Y.,Sacchettini, J.C.
The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD.
Nat Commun, 11:339-339, 2020

PubMed Abstract: Pyrazinamide has been a mainstay in the multidrug regimens used to treat tuberculosis. It is active against the persistent, non-replicating mycobacteria responsible for the protracted therapy required to cure tuberculosis. Pyrazinamide is a pro-drug that is converted into pyrazinoic acid (POA) by pyrazinamidase, however, the exact target of the drug has been difficult to determine. Here we show the enzyme PanD binds POA in its active site in a manner consistent with competitive inhibition. The active site is not directly accessible to the inhibitor, suggesting the protein must undergo a conformational change to bind the inhibitor. This is consistent with the slow binding kinetics we determined for POA. Drug-resistant mutations cluster near loops that lay on top of the active site. These resistant mutants show reduced affinity and residence time of POA consistent with a model where resistance occurs by destabilizing the closed conformation of the active site.

PubMed: 31953389
DOI: 10.1038/s41467-019-14238-3

Experimental method

X-RAY DIFFRACTION (2.7 Å)