6B3V

PANK3 complex with compound PZ-2891

Summary for 6B3V

• Entry DOI: 10.2210/pdb6b3v/pdb
• Related: 5TL3
• Descriptor: Pantothenate kinase 3, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: pank, inhibitor, complex, transferase, pantothenate kinase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 43129.82

Authors

White, S.W.,Yun, M. (deposition date: 2017-09-25, release date: 2018-08-29, Last modification date: 2023-10-04)

Primary citation

Sharma, L.K.,Subramanian, C.,Yun, M.K.,Frank, M.W.,White, S.W.,Rock, C.O.,Lee, R.E.,Jackowski, S.
A therapeutic approach to pantothenate kinase associated neurodegeneration.
Nat Commun, 9:4399-4399, 2018

PubMed Abstract: Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.

PubMed: 30352999
DOI: 10.1038/s41467-018-06703-2

Experimental method

X-RAY DIFFRACTION (1.601 Å)