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- PDB-6i0m: Structure of human IMP dehydrogenase, isoform 2, bound to GDP -

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Basic information

Entry
Database: PDB / ID: 6i0m
TitleStructure of human IMP dehydrogenase, isoform 2, bound to GDP
ComponentsInosine-5'-monophosphate dehydrogenase 2
KeywordsBIOSYNTHETIC PROTEIN / oxidoreductase / de novo guanine nucleotide biosynthesis
Function / homology
Function and homology information


lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 ...lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 / circadian rhythm / retina development in camera-type eye / Potential therapeutics for SARS / secretory granule lumen / ficolin-1-rich granule lumen / nucleotide binding / Neutrophil degranulation / RNA binding / DNA binding / extracellular exosome / extracellular region / membrane / metal ion binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Inosine-5'-monophosphate dehydrogenase / IMP dehydrogenase / GMP reductase, conserved site / IMP dehydrogenase / GMP reductase signature. / IMP dehydrogenase / GMP reductase domain / IMP dehydrogenase/GMP reductase / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / Aldolase class I ...Inosine-5'-monophosphate dehydrogenase / IMP dehydrogenase / GMP reductase, conserved site / IMP dehydrogenase / GMP reductase signature. / IMP dehydrogenase / GMP reductase domain / IMP dehydrogenase/GMP reductase / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-MONOPHOSPHATE / GUANOSINE-5'-DIPHOSPHATE / Inosine-5'-monophosphate dehydrogenase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.567 Å
AuthorsBuey, R.M. / Fernandez-Justel, D. / Revuelta, J.L.
Funding support Spain, 1items
OrganizationGrant numberCountry
BFU2016-79237-P Spain
CitationJournal: J Mol Biol / Year: 2019
Title: A Nucleotide-Dependent Conformational Switch Controls the Polymerization of Human IMP Dehydrogenases to Modulate their Catalytic Activity.
Authors: David Fernández-Justel / Rafael Núñez / Jaime Martín-Benito / David Jimeno / Adrián González-López / Eva María Soriano / José Luis Revuelta / Rubén M Buey /
Abstract: Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH ...Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH has been studied for decades, but it has only been within the last years that we are starting to understand the complexity of the mechanisms of its physiological regulation. Here, we report structural and functional insights into how adenine and guanine nucleotides control a conformational switch that modulates the assembly of the two human IMPDH enzymes into cytoophidia and allosterically regulates their catalytic activity. In vitro reconstituted micron-length cytoophidia-like structures show catalytic activity comparable to unassembled IMPDH but, in turn, are more resistant to GTP/GDP allosteric inhibition. Therefore, IMPDH cytoophidia formation facilitates the accumulation of high levels of guanine nucleotides when the cell requires it. Finally, we demonstrate that most of the IMPDH retinopathy-associated mutations abrogate GTP/GDP-induced allosteric inhibition and alter cytoophidia dynamics.
History
DepositionOct 26, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 30, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Inosine-5'-monophosphate dehydrogenase 2
B: Inosine-5'-monophosphate dehydrogenase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,66120
Polymers112,3142
Non-polymers4,34618
Water1,33374
1
A: Inosine-5'-monophosphate dehydrogenase 2
B: Inosine-5'-monophosphate dehydrogenase 2
hetero molecules

A: Inosine-5'-monophosphate dehydrogenase 2
B: Inosine-5'-monophosphate dehydrogenase 2
hetero molecules

A: Inosine-5'-monophosphate dehydrogenase 2
B: Inosine-5'-monophosphate dehydrogenase 2
hetero molecules

A: Inosine-5'-monophosphate dehydrogenase 2
B: Inosine-5'-monophosphate dehydrogenase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)466,64280
Polymers449,2578
Non-polymers17,38572
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_795-x+2,-y+4,z1
crystal symmetry operation3_865-y+3,x+1,z1
crystal symmetry operation4_485y-1,-x+3,z1
Buried area64970 Å2
ΔGint-929 kcal/mol
Surface area130460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)134.729, 134.729, 324.081
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422

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Components

#1: Protein Inosine-5'-monophosphate dehydrogenase 2 / IMPDH 2 / IMPDH-II


Mass: 56157.137 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IMPDH2, IMPD2 / Production host: Escherichia coli BL21(DE3) (unknown) / References: UniProt: P12268, IMP dehydrogenase
#2: Chemical ChemComp-5GP / GUANOSINE-5'-MONOPHOSPHATE / Guanosine monophosphate


Mass: 363.221 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H14N5O8P
#3: Chemical
ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.27 Å3/Da / Density % sol: 62.43 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.1 M sodium citrate, pH 5.5 0.2 M lithium sulphate 15% (v/v) ethanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 10, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.567→162 Å / Num. obs: 48045 / % possible obs: 94.9 % / Redundancy: 25.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.194 / Rpim(I) all: 0.039 / Rrim(I) all: 0.198 / Net I/σ(I): 14.6
Reflection shellResolution: 2.567→2.753 Å / Redundancy: 27.1 % / Rmerge(I) obs: 2.617 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 517 / CC1/2: 0.629 / Rpim(I) all: 0.517 / Rrim(I) all: 2.696 / % possible all: 64.2

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Processing

Software
NameVersionClassification
PHENIX(1.12rc1_2801: ???)refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Z87
Resolution: 2.567→162 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2487 1967 5.04 %
Rwork0.2187 --
obs0.2203 39034 81.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.567→162.041 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6430 0 266 76 6772
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0036897
X-RAY DIFFRACTIONf_angle_d0.6579404
X-RAY DIFFRACTIONf_dihedral_angle_d13.613959
X-RAY DIFFRACTIONf_chiral_restr0.0441098
X-RAY DIFFRACTIONf_plane_restr0.0031159
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
13.6153-0.8965-1.17923.70981.16681.7218-0.0633-0.4422-0.0640.01410.00580.4561-0.1033-0.0839-0.00030.4236-0.0336-0.0240.4047-0.0070.5003149.7683287.2276405.1394
22.06050.2038-1.29720.5252-0.72191.9601-0.11480.1475-0.2329-0.24820.1565-0.23470.04090.26070.00020.4303-0.06230.05960.5228-0.12740.608176.3227282.6215383.9359
30.0459-0.0406-0.01220.4354-0.38540.67710.39380.8115-1.0132-0.3797-0.12520.11141.3688-0.50330.02620.9364-0.19330.13340.9709-0.13020.8205193.3945291.0383372.0579
41.65370.78910.06363.0186-0.13111.2822-0.18480.279-0.0048-0.25610.1232-0.4461-0.19590.2322-0.00120.4438-0.08370.06540.6146-0.08460.5424186.8518293.5618381.7624
52.80942.2512-1.31414.4945-1.41052.4615-0.0241-0.1442-0.1931-0.0227-0.0511-0.28930.00550.21040.00250.3335-0.0158-0.07010.389-0.03930.54170.7427269.8703400.7966
63.10150.1999-0.87331.7706-1.96992.20810.2481-0.1808-0.15850.2851-0.23320.32730.6008-0.442200.3745-0.0299-0.11960.385-0.02850.5689156.8268271.8652405.4168
71.2771.4697-2.2291.9534-0.95252.0899-0.0880.56960.112-0.56540.05330.01120.2163-0.5469-0.01960.45460.0325-0.05760.4542-0.06060.5556158.6496279.881387.5637
81.8435-0.94370.67242.2583-1.89361.743-0.04930.3628-0.1605-0.6231-0.15310.7450.13720.29190.00220.5558-0.01360.00360.6482-0.01860.6291156.1058285.1857387.3037
92.43420.4004-1.8741.6153-1.53793.00830.09250.1820.41970.0207-0.07090.4337-0.1313-0.30110.00020.4601-0.0215-0.00350.4588-0.07770.615147.2548286.1968404.4497
100.26340.0185-0.03234.65920.19681.38850.2252-0.01430.12360.0098-0.08750.07370.17210.0114-0.00030.6386-0.0363-0.03760.78460.01950.3791155.9421278.6819337.2808
110.8985-1.08611.41112.82460.71282.8819-0.0821-0.09430.08450.4037-0.17330.0046-0.3633-0.006-00.7702-0.1418-0.08230.6681-0.04970.5509157.5741303.7344356.9733
120.8676-0.0076-0.56580.39220.18990.59080.08930.71371.09280.94230.26061.2332-0.8443-0.56650.01811.4324-0.1368-0.14410.7037-0.0910.9407172.1441320.1418370.9848
131.9432-0.77050.9350.6762-0.07530.4015-0.17090.21510.72340.01870.05240.1178-1.01961.08750.00341.1002-0.3229-0.17090.878-0.03281.1527182.0087315.1781366.9599
142.571.43521.57090.38610.10051.1669-0.0255-0.21230.46490.1449-0.0865-0.1196-0.2040.1018-00.8467-0.076-0.08520.6976-0.04760.7296159.1769309.3873351.4844
152.26210.37110.86881.00710.91251.76910.00530.3050.19860.00260.1026-0.0667-0.3875-0.302-0.00010.7351-0.0448-0.03650.63150.04490.5365146.0122300.8129340.5422
162.66950.50641.97193.54580.39391.6377-0.1723-0.17640.2930.08550.0689-0.1781-0.0826-0.1088-0.00550.5425-0.02240.03450.57560.02080.4451147.435288.9481341.676
170.1170.2305-0.1166-0.0113-0.09850.3336-0.633-1.2923-0.871-0.1040.4374-0.56220.39560.6064-0.00041.04730.0580.04341.08810.09340.7368152.3926290.5119369.0399
181.9052-0.55471.37021.61430.92933.0154-0.03770.2004-0.00380.20870.167-0.25020.11610.6144-0.00020.61160.0297-0.08350.60770.00990.485157.8636279.1666345.1035
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 58 )
2X-RAY DIFFRACTION2chain 'A' and (resid 59 through 126 )
3X-RAY DIFFRACTION3chain 'A' and (resid 127 through 158 )
4X-RAY DIFFRACTION4chain 'A' and (resid 159 through 265 )
5X-RAY DIFFRACTION5chain 'A' and (resid 266 through 333 )
6X-RAY DIFFRACTION6chain 'A' and (resid 334 through 357 )
7X-RAY DIFFRACTION7chain 'A' and (resid 358 through 414 )
8X-RAY DIFFRACTION8chain 'A' and (resid 415 through 471 )
9X-RAY DIFFRACTION9chain 'A' and (resid 472 through 502 )
10X-RAY DIFFRACTION10chain 'B' and (resid 11 through 58 )
11X-RAY DIFFRACTION11chain 'B' and (resid 59 through 119 )
12X-RAY DIFFRACTION12chain 'B' and (resid 120 through 158 )
13X-RAY DIFFRACTION13chain 'B' and (resid 159 through 204 )
14X-RAY DIFFRACTION14chain 'B' and (resid 205 through 293 )
15X-RAY DIFFRACTION15chain 'B' and (resid 294 through 332 )
16X-RAY DIFFRACTION16chain 'B' and (resid 333 through 386 )
17X-RAY DIFFRACTION17chain 'B' and (resid 387 through 452 )
18X-RAY DIFFRACTION18chain 'B' and (resid 453 through 514 )

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