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- PDB-6i0o: Structure of human IMP dehydrogenase, isoform 2, bound to GTP -

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Basic information

Entry
Database: PDB / ID: 6i0o
TitleStructure of human IMP dehydrogenase, isoform 2, bound to GTP
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 signature. / IMP dehydrogenase / GMP reductase, conserved site / 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 signature. / IMP dehydrogenase / GMP reductase, conserved site / 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'-TRIPHOSPHATE / Inosine-5'-monophosphate dehydrogenase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.623 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 1.1Feb 20, 2019Group: Advisory / Data collection / Derived calculations
Category: diffrn_source / pdbx_data_processing_status ...diffrn_source / pdbx_data_processing_status / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_close_contact / struct_conn / struct_conn_type
Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2Mar 6, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jul 10, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site

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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)117,95134
Polymers112,3142
Non-polymers5,63732
Water1,60389
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)471,804136
Polymers449,2578
Non-polymers22,547128
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_445-x-1,-y-1,z1
crystal symmetry operation3_455-y-1,x,z1
crystal symmetry operation4_545y,-x-1,z1
Buried area67990 Å2
ΔGint-1658 kcal/mol
Surface area126460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)134.119, 134.119, 325.703
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-GTP / GUANOSINE-5'-TRIPHOSPHATE / Guanosine triphosphate


Mass: 523.180 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#3: Chemical...
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 26 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 89 / 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: 3.26 Å3/Da / Density % sol: 62.27 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 25% (w/v) PEG-1500 0.1 M Buffer MIB (malonic acid, imadazole, boric acid), pH 9.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.99987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 21, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 2.623→81.953 Å / Num. obs: 44889 / % possible obs: 92.6 % / Redundancy: 6.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.142 / Rpim(I) all: 0.06 / Rrim(I) all: 0.155 / Net I/σ(I): 10.6
Reflection shellResolution: 2.623→2.827 Å / Redundancy: 7 % / Rmerge(I) obs: 1.564 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 353 / CC1/2: 0.408 / Rpim(I) all: 0.635 / Rrim(I) all: 1.689 / % possible all: 47

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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: 2.623→81.953 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2437 1844 5.06 %
Rwork0.2193 --
obs0.2206 36415 81.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.623→81.953 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6340 0 322 89 6751
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0036720
X-RAY DIFFRACTIONf_angle_d0.6159177
X-RAY DIFFRACTIONf_dihedral_angle_d14.2453887
X-RAY DIFFRACTIONf_chiral_restr0.0431063
X-RAY DIFFRACTIONf_plane_restr0.0031128
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.623-2.69390.2804110.2996196X-RAY DIFFRACTION6
2.6939-2.77320.3139380.3032702X-RAY DIFFRACTION22
2.7732-2.86270.3346910.31181508X-RAY DIFFRACTION47
2.8627-2.9650.34091360.30342472X-RAY DIFFRACTION77
2.965-3.08380.34481890.2913196X-RAY DIFFRACTION99
3.0838-3.22410.28941650.28333245X-RAY DIFFRACTION100
3.2241-3.39410.26381780.26273248X-RAY DIFFRACTION100
3.3941-3.60680.23071580.22723281X-RAY DIFFRACTION100
3.6068-3.88520.23311850.21313256X-RAY DIFFRACTION100
3.8852-4.27620.20871680.1893280X-RAY DIFFRACTION100
4.2762-4.89490.20111560.1693322X-RAY DIFFRACTION100
4.8949-6.16680.22791640.20973365X-RAY DIFFRACTION100
6.1668-81.99280.24982050.2173500X-RAY DIFFRACTION100
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)
12.554-0.3972-0.54090.6609-0.5790.6503-0.09740.1285-0.1427-0.04450.0025-0.14870.0049-0.0595-00.6917-0.07110.02020.65280.00470.4507-46.1679-46.0051-23.2293
20.1510.06930.17860.33140.22890.28020.08360.0168-0.00850.5688-0.1923-0.8710.62280.9320.00410.7415-0.00720.08741.12550.17270.9485-18.9637-31.5522-45.3425
30.7380.10610.03390.84860.22490.2263-0.09520.1425-0.01760.0189-0.1734-0.2992-0.13790.34870.00740.82740.010.12161.10270.13560.9738-17.8847-25.7854-49.403
41.2066-0.07520.11260.6784-0.39950.826-0.1092-0.36390.75920.2945-0.2213-0.7033-0.37350.3891-0.19490.9265-0.26590.04760.98380.23831.0034-20.7269-17.0712-37.7138
51.31720.7105-0.27680.7428-0.79350.9224-0.25490.0708-0.00470.36870.1775-0.0606-0.239-0.0313-0.00190.6903-0.06670.04270.74830.09140.572-26.6636-35.2087-31.6162
61.4362-1.04460.03131.6831-0.86321.8212-0.09860.0971-0.23930.0599-0.0155-0.77140.18890.2495-00.6387-0.03920.00270.63010.02560.5781-33.2629-57.0818-17.4728
70.83840.6863-0.34270.5978-0.34280.17580.00040.1950.2188-0.069-0.05250.0863-0.1801-0.0335-00.7203-0.0337-0.11450.7168-0.03580.474-46.043-52.9328-14.0808
80.0983-0.1730.27160.1644-0.22770.47850.09910.30610.3523-0.4593-0.0419-0.05810.15950.0779-0.03280.8352-0.0358-0.00770.7486-0.00110.6066-47.8683-48.353-32.9287
91.0505-0.72040.07761.4123-0.92561.25420.03940.33070.2019-0.0908-0.00070.0729-0.4773-0.0614-0.00020.5842-0.00230.01780.58360.06140.3785-57.1007-43.651-19.1971
101.19620.17860.12132.56420.69330.78210.1104-0.0957-0.00170.1959-0.1260.15370.063-0.13600.406-0.04030.05210.37230.02770.4617-52.3051-36.2193-68.9129
111.1083-0.3482-0.49070.36610.15171.1225-0.3712-0.8660.01010.44940.4197-0.02550.3654-0.5840.00390.9125-0.04470.14330.7749-0.15710.7781-43.4946-8.5144-44.7146
121.72081.4317-0.04032.99630.75671.06580.1445-0.16220.22380.1874-0.1308-0.0629-0.00720.04680.00460.5557-0.04320.06050.49-0.00540.5347-43.6763-15.3942-61.2567
132.42750.48290.28581.59740.24751.55830.0467-0.04130.02370.14130.020.10060.04020.03940.00120.3501-0.04650.06380.28970.02520.4753-58.1454-40.7564-74.9317
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 110 )
2X-RAY DIFFRACTION2chain 'A' and (resid 111 through 137 )
3X-RAY DIFFRACTION3chain 'A' and (resid 138 through 174 )
4X-RAY DIFFRACTION4chain 'A' and (resid 175 through 204 )
5X-RAY DIFFRACTION5chain 'A' and (resid 205 through 266 )
6X-RAY DIFFRACTION6chain 'A' and (resid 267 through 342 )
7X-RAY DIFFRACTION7chain 'A' and (resid 343 through 369 )
8X-RAY DIFFRACTION8chain 'A' and (resid 370 through 452 )
9X-RAY DIFFRACTION9chain 'A' and (resid 453 through 499 )
10X-RAY DIFFRACTION10chain 'B' and (resid 11 through 126 )
11X-RAY DIFFRACTION11chain 'B' and (resid 127 through 174 )
12X-RAY DIFFRACTION12chain 'B' and (resid 175 through 266 )
13X-RAY DIFFRACTION13chain 'B' and (resid 267 through 497 )

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