8G9C

Diphosphoinositol polyphosphate phosphohydrolase 1 (DIPP1/NUDT3) in complex with 5- difluoromethylenebisphosphonate inositol pentakisphosphate (5-PCF2P-IP5), an analogue of 5-InsP7

PDB DOI: https://doi.org/10.2210/pdb8G9C/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2023-02-21 Released: 2024-01-03
Deposition Author(s): Zong, G., Wang, H., Shears, S.
Funding Organization(s): National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.40 ?
R-Value Free: 0.188
R-Value Work: 0.170
R-Value Observed: 0.170

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.0 of the entry. See complete history.

Literature

Fluorination Influences the Bioisostery of Myo-Inositol Pyrophosphate Analogs.

Hostachy, S., Wang, H., Zong, G., Franke, K., Riley, A.M., Schmieder, P., Potter, B.V.L., Shears, S.B., Fiedler, D.

(2023) Chemistry 29: e202302426-e202302426

PubMed: 37773020 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/chem.202302426
Primary Citation of Related Structures:
8G9C, 8G9D, 8G9E

PubMed Abstract:
Inositol pyrophosphates (PP-IPs) are densely phosphorylated messenger molecules involved in numerous biological processes. PP-IPs contain one or two pyrophosphate group(s) attached to a phosphorylated myo-inositol ring. 5PP-IP ₅ is the most abundant PP-IP in human cells. To investigate the function and regulation by PP-IPs in biological contexts, metabolically stable analogs have been developed. Here, we report the synthesis of a new fluorinated phosphoramidite reagent and its application for the synthesis of a difluoromethylene bisphosphonate analog of 5PP-IP ₅ . Subsequently, the properties of all currently reported analogs were benchmarked using a number of biophysical and biochemical methods, including co-crystallization, ITC, kinase activity assays and chromatography. Together, the results showcase how small structural alterations of the analogs can have notable effects on their properties in a biochemical setting and will guide in the choice of the most suitable analog(s) for future investigations.

Organizational Affiliation

Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-R?ssle-Stra?e 10, 13125, Berlin, Germany.

Macromolecule Content

Total Structure Weight: 20.46 kDa
Atom Count: 1,294
Modelled Residue Count: 134
Deposited Residue Count: 172
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Diphosphoinositol polyphosphate phosphohydrolase 1	A	172	Homo sapiens	Mutation(s): 0 Gene Names: NUDT3, DIPP, DIPP1 EC: 3.6.1.52 (PDB Primary Data), 3.6.1 (PDB Primary Data), 3.6.1.62 (UniProt), 3.6.1.61 (UniProt), 3.6.1.59 (UniProt), 3.6.1.10 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for O95989 (Homo sapiens) Explore O95989 Go to UniProtKB: O95989
PHAROS: O95989 GTEx: ENSG00000272325
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O95989
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
YUT (Subject of Investigation/LOI) Query on YUT 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]	{difluoro[(R)-hydroxy{[(1s,2R,3S,4S,5R,6S)-2,3,4,5,6-pentakis(phosphonooxy)cyclohexyl]oxy}phosphoryl]methyl}phosphonic acid C₇ H₁₉ F₂ O₂₆ P₇ WXRZISRVPNTHSS-QWBQGLJISA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A]	G [auth A], H [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain G [auth A] Focus chain H [auth A] Interactions & Density Focus chain G [auth A] Focus chain H [auth A]
MG (Subject of Investigation/LOI) Query on MG Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	C [auth A], D [auth A], E [auth A], F [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A]
F Query on F Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A] mmCIF format, chain I [auth A]	I [auth A]	FLUORIDE ION F KRHYYFGTRYWZRS-UHFFFAOYSA-M		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]