6B3V

PANK3 complex with compound PZ-2891

PDB DOI: https://doi.org/10.2210/pdb6B3V/pdb

Classification: TRANSFERASE/INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2017-09-25 Released: 2018-08-29
Deposition Author(s): White, S.W., Yun, M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.60 ?
R-Value Free:
0.195 (Depositor), 0.200 (DCC)
R-Value Work:
0.178 (Depositor), 0.180 (DCC)
R-Value Observed:
0.178 (Depositor)

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

A therapeutic approach to pantothenate kinase associated neurodegeneration.

Sharma, L.K., Subramanian, C., Yun, M.K., Frank, M.W., White, S.W., Rock, C.O., Lee, R.E., Jackowski, S.

(2018) Nat Commun 9: 4399-4399

PubMed: 30352999 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/s41467-018-06703-2
Primary Citation of Related Structures:
6B3V

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 ²⁺?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.

Organizational Affiliation

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Macromolecule Content

Total Structure Weight: 43.13 kDa
Atom Count: 2,934
Modelled Residue Count: 352
Deposited Residue Count: 380
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Pantothenate kinase 3	A	380	Homo sapiens	Mutation(s): 0 Gene Names: PANK3 EC: 2.7.1.33
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H999 (Homo sapiens) Explore Q9H999 Go to UniProtKB: Q9H999
PHAROS: Q9H999 GTEx: ENSG00000120137
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9H999
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
ANP Query on ANP Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER C₁₀ H₁₇ N₆ O₁₂ P₃ PVKSNHVPLWYQGJ-KQYNXXCUSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
7DQ (Subject of Investigation/LOI) Query on 7DQ Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	6-(4-{[4-(propan-2-yl)phenyl]acetyl}piperazin-1-yl)pyridazine-3-carbonitrile C₂₀ H₂₃ N₅ O LGWDVWIZDPGCFG-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A]	D [auth A], E [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Interactions & Density Focus chain D [auth A] Focus chain E [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
7DQ	BindingDB: 6B3V	IC50: 1 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.60 ?
R-Value Free: 0.195 (Depositor), 0.200 (DCC)
R-Value Work: 0.178 (Depositor), 0.180 (DCC)
R-Value Observed: 0.178 (Depositor)

Space Group: P 3₁ 2 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 98.874	α = 90
b = 98.874	β = 90
c = 69.117	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
HKL-2000	data reduction
HKL-2000	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2018-08-29

Deposition Author(s):

White, S.W.

Yun, M.

Revision History (Full details and data files)

Version 1.0: 2018-08-29
Type: Initial release
Version 1.1: 2018-11-28
Changes: Data collection, Database references
Version 1.2: 2023-10-04
Changes: Data collection, Database references, Derived calculations, Refinement description