6GIU

Human IMPase with L-690330

PDB DOI: https://doi.org/10.2210/pdb6GIU/pdb

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

Deposited: 2018-05-15 Released: 2018-10-17
Deposition Author(s): Kraft, L.V., Roe, S.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.39 Å
R-Value Free: 0.167
R-Value Work: 0.148
R-Value Observed: 0.149

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330.

Kraft, L., Roe, S.M., Gill, R., Atack, J.R.

(2018) Acta Crystallogr D Struct Biol 74: 973-978

PubMed: 30289407 Search on PubMed
DOI: https://doi.org/10.1107/S2059798318010380
Primary Citation of Related Structures:
6GIU, 6GJ0

PubMed Abstract:
Lithium, which is still the gold standard in the treatment of bipolar disorder, has been proposed to inhibit inositol monophosphatase (IMPase) and is hypothesized to exert its therapeutic effects by attenuating phosphatidylinositol (PI) cell signalling. Drug-discovery efforts have focused on small-molecule lithium mimetics that would specifically inhibit IMPase without exhibiting the undesired side effects of lithium. L-690,330 is a potent bisphosphonate substrate-based inhibitor developed by Merck Sharp & Dohme. To aid future structure-based inhibitor design, determination of the exact binding mechanism of L-690,330 to IMPase was of interest. Here, the high-resolution X-ray structure of human IMPase in complex with L690,330 and manganese ions determined at 1.39 Å resolution is reported.

Organizational Affiliation

Sussex Drug Discovery Centre, University of Sussex, Chichester II, Falmer, Brighton BN1 9QJ, England.

Macromolecule Content

Total Structure Weight: 63.17 kDa
Atom Count: 5,141
Modelled Residue Count: 550
Deposited Residue Count: 554
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Inositol monophosphatase 1	A, B	277	Homo sapiens	Mutation(s): 0 Gene Names: IMPA1, IMPA EC: 3.1.3.25 (PDB Primary Data), 3.1.3.94 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P29218 (Homo sapiens) Explore P29218 Go to UniProtKB: P29218
PHAROS: P29218 GTEx: ENSG00000133731
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P29218
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
L69 (Subject of Investigation/LOI) Query on L69 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain W [auth B] MOL2 format, chain F [auth A] MOL2 format, chain W [auth B] mmCIF format, chain F [auth A] mmCIF format, chain W [auth B]	F [auth A], W [auth B]	[1-(4-oxidanylphenoxy)-1-phosphono-ethyl]phosphonic acid C₈ H₁₂ O₈ P₂ JKOCAAWWDVHWKB-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain W [auth B] Interactions & Density Focus chain F [auth A] Focus chain W [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain AA [auth B] SDF format, chain CA [auth B] SDF format, chain DA [auth B] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain P [auth A] SDF format, chain Q [auth A] SDF format, chain R [auth A] SDF format, chain X [auth B] SDF format, chain BA [auth B] SDF format, chain L [auth A] SDF format, chain O [auth A] SDF format, chain Y [auth B] SDF format, chain Z [auth B] MOL2 format, chain AA [auth B] MOL2 format, chain CA [auth B] MOL2 format, chain DA [auth B] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain P [auth A] MOL2 format, chain Q [auth A] MOL2 format, chain R [auth A] MOL2 format, chain X [auth B] MOL2 format, chain BA [auth B] MOL2 format, chain L [auth A] MOL2 format, chain O [auth A] MOL2 format, chain Y [auth B] MOL2 format, chain Z [auth B] mmCIF format, chain AA [auth B] mmCIF format, chain CA [auth B] mmCIF format, chain DA [auth B] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain P [auth A] mmCIF format, chain Q [auth A] mmCIF format, chain R [auth A] mmCIF format, chain X [auth B] mmCIF format, chain BA [auth B] mmCIF format, chain L [auth A] mmCIF format, chain O [auth A] mmCIF format, chain Y [auth B] mmCIF format, chain Z [auth B]	AA [auth B] BA [auth B] CA [auth B] DA [auth B] G [auth A] AA [auth B], BA [auth B], CA [auth B], DA [auth B], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], L [auth A], M [auth A], N [auth A], O [auth A], P [auth A], Q [auth A], R [auth A], X [auth B], Y [auth B], Z [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain AA [auth B] Focus chain BA [auth B] Focus chain CA [auth B] Focus chain DA [auth B] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain P [auth A] Focus chain Q [auth A] Focus chain R [auth A] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B] Interactions & Density Focus chain AA [auth B] Focus chain BA [auth B] Focus chain CA [auth B] Focus chain DA [auth B] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain P [auth A] Focus chain Q [auth A] Focus chain R [auth A] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B]
MN Query on MN Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain S [auth B] SDF format, chain U [auth B] SDF format, chain V [auth B] SDF format, chain E [auth A] SDF format, chain T [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain S [auth B] MOL2 format, chain U [auth B] MOL2 format, chain V [auth B] MOL2 format, chain E [auth A] MOL2 format, chain T [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain S [auth B] mmCIF format, chain U [auth B] mmCIF format, chain V [auth B] mmCIF format, chain E [auth A] mmCIF format, chain T [auth B]	C [auth A] D [auth A] E [auth A] S [auth B] T [auth B] C [auth A], D [auth A], E [auth A], S [auth B], T [auth B], U [auth B], V [auth B]	MANGANESE (II) ION Mn WAEMQWOKJMHJLA-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
L69	BindingDB: 6GIU	IC50: 330 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.39 Å
R-Value Free: 0.167
R-Value Work: 0.148
R-Value Observed: 0.149
Space Group: P 3₂ 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 85.29	α = 90
b = 85.29	β = 90
c = 151.51	γ = 120

Software Package:

Software Name	Purpose
BUSTER	refinement
xia2	data reduction
xia2	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2018-10-17

Deposition Author(s):

Kraft, L.V.

Roe, S.M.

Funding Organization	Location	Grant Number
	United Kingdom	--

Revision History (Full details and data files)

Version 1.0: 2018-10-17
Type: Initial release
Version 1.1: 2024-01-17
Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description, Structure summary