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- PDB-5nx9: Crystal structure of Neanderthal Adenylosuccinate Lyase (ADSL) in... -

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Basic information

Entry
Database: PDB / ID: 5nx9
TitleCrystal structure of Neanderthal Adenylosuccinate Lyase (ADSL) in complex with its products AMP and fumarate
ComponentsAdenylosuccinate lyase
KeywordsLYASE / Adenylosuccinate Lyase / fumarase
Function / homology
Function and homology information


adenylosuccinate lyase / N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity / (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity / 'de novo' AMP biosynthetic process / 'de novo' IMP biosynthetic process
Similarity search - Function
Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #1570 / Adenylosuccinate lyase C-terminus / Adenylosuccinate lyase C-terminal / Adenylosuccinate lyase C-terminus / Adenylosuccinate lyase / Fumarate lyase, conserved site / Fumarate lyases signature. / Fumarate lyase family / Fumarate lyase, N-terminal / Lyase ...Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #1570 / Adenylosuccinate lyase C-terminus / Adenylosuccinate lyase C-terminal / Adenylosuccinate lyase C-terminus / Adenylosuccinate lyase / Fumarate lyase, conserved site / Fumarate lyases signature. / Fumarate lyase family / Fumarate lyase, N-terminal / Lyase / Fumarase/aspartase (N-terminal domain) / Fumarase/aspartase (Central domain) / Fumarase C; Chain A, domain 2 / Fumarase C; Chain B, domain 1 / L-Aspartase-like / Single alpha-helices involved in coiled-coils or other helix-helix interfaces / Helix non-globular / Special / Up-down Bundle / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-2SA / ADENOSINE MONOPHOSPHATE / FUMARIC ACID / DI(HYDROXYETHYL)ETHER / Adenylosuccinate lyase
Similarity search - Component
Biological speciesHomo sapiens neanderthalensis (Neandertal)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsVan Laer, B. / Kapp, U. / Soler-Lopez, M. / Leonard, G. / Mueller-Dieckmann, C.
CitationJournal: Sci Rep / Year: 2018
Title: Molecular comparison of Neanderthal and Modern Human adenylosuccinate lyase.
Authors: Bart Van Laer / Ulrike Kapp / Montserrat Soler-Lopez / Kaja Moczulska / Svante Pääbo / Gordon Leonard / Christoph Mueller-Dieckmann /
Abstract: The availability of genomic data from extinct homini such as Neanderthals has caused a revolution in palaeontology allowing the identification of modern human-specific protein substitutions. ...The availability of genomic data from extinct homini such as Neanderthals has caused a revolution in palaeontology allowing the identification of modern human-specific protein substitutions. Currently, little is known as to how these substitutions alter the proteins on a molecular level. Here, we investigate adenylosuccinate lyase, a conserved enzyme involved in purine metabolism for which several substitutions in the modern human protein (hADSL) have been described to affect intelligence and behaviour. During evolution, modern humans acquired a specific substitution (Ala429Val) in ADSL distinguishing it from the ancestral variant present in Neanderthals (nADSL). We show here that despite this conservative substitution being solvent exposed and located distant from the active site, there is a difference in thermal stability, but not enzymology or ligand binding between nADSL and hADSL. Substitutions near residue 429 which do not profoundly affect enzymology were previously reported to cause neurological symptoms in humans. This study also reveals that ADSL undergoes conformational changes during catalysis which, together with the crystal structure of a hitherto undetermined product bound conformation, explains the molecular origin of disease for several modern human ADSL mutants.
History
DepositionMay 9, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 30, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 30, 2019Group: Data collection / Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Refinement description
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 2.1Jan 17, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Adenylosuccinate lyase
B: Adenylosuccinate lyase
C: Adenylosuccinate lyase
D: Adenylosuccinate lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)224,40330
Polymers220,8664
Non-polymers3,53826
Water7,152397
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: SAXS, SAXS and size exclusion chromatography confirm tetrameric structure.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area40880 Å2
ΔGint-134 kcal/mol
Surface area60870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.740, 107.490, 209.660
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERALAALAAA9 - 48012 - 483
21SERSERALAALABB9 - 48012 - 483
12SERSERTYRTYRAA9 - 47212 - 475
22SERSERTYRTYRCC9 - 47212 - 475
13SERSERALAALAAA9 - 48012 - 483
23SERSERALAALADD9 - 48012 - 483
14SERSERTYRTYRBB9 - 47212 - 475
24SERSERTYRTYRCC9 - 47212 - 475
15GLYGLYLEULEUBB8 - 48211 - 485
25GLYGLYLEULEUDD8 - 48211 - 485
16SERSERTYRTYRCC9 - 47212 - 475
26SERSERTYRTYRDD9 - 47212 - 475

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Adenylosuccinate lyase /


Mass: 55216.445 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens neanderthalensis (Neandertal)
Plasmid: pET14b / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta 2
References: UniProt: A0A384E0N4*PLUS, adenylosuccinate lyase

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Non-polymers , 7 types, 423 molecules

#2: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-AMP / ADENOSINE MONOPHOSPHATE / Adenosine monophosphate


Mass: 347.221 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM
#4: Chemical ChemComp-FUM / FUMARIC ACID / Fumaric acid


Mass: 116.072 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H4O4
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-2SA / 2-[9-(3,4-DIHYDROXY-5-PHOSPHONOOXYMETHYL-TETRAHYDRO-FURAN-2-YL)-9H-PURIN-6-YLAMINO]-SUCCINIC ACID / ADENYLOSUCCINIC ACID


Type: RNA linking / Mass: 463.293 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H18N5O11P
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 397 / 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: 2.2 Å3/Da / Density % sol: 58 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 25% PEG1000, 0.1 M MES pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.967 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Nov 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.967 Å / Relative weight: 1
ReflectionResolution: 2.3→48.38 Å / Num. obs: 86413 / % possible obs: 99.6 % / Redundancy: 3.8 % / Biso Wilson estimate: 38 Å2 / CC1/2: 0.986 / Rrim(I) all: 0.235 / Net I/σ(I): 5.7
Reflection shellResolution: 2.3→2.4 Å / Mean I/σ(I) obs: 1.2 / Num. unique obs: 12466 / CC1/2: 0.356 / Rrim(I) all: 1.389 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5NX8

5nx8


Resolution: 2.3→48.38 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.935 / SU B: 9.908 / SU ML: 0.219 / Cross valid method: THROUGHOUT / ESU R: 0.397 / ESU R Free: 0.231 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22654 4317 5 %RANDOM
Rwork0.19342 ---
obs0.19506 82019 99.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 40.803 Å2
Baniso -1Baniso -2Baniso -3
1--1.03 Å2-0 Å20 Å2
2--0.97 Å2-0 Å2
3---0.06 Å2
Refinement stepCycle: 1 / Resolution: 2.3→48.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14840 0 227 397 15464
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01915321
X-RAY DIFFRACTIONr_bond_other_d0.0010.0214478
X-RAY DIFFRACTIONr_angle_refined_deg1.2321.97820654
X-RAY DIFFRACTIONr_angle_other_deg0.812333550
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9251853
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.78923.61712
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.837152791
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.23115135
X-RAY DIFFRACTIONr_chiral_restr0.0730.22324
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02116723
X-RAY DIFFRACTIONr_gen_planes_other0.0030.023112
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.7543.8477433
X-RAY DIFFRACTIONr_mcbond_other2.7543.8467432
X-RAY DIFFRACTIONr_mcangle_it4.1965.7639279
X-RAY DIFFRACTIONr_mcangle_other4.1965.7649280
X-RAY DIFFRACTIONr_scbond_it4.0384.3847888
X-RAY DIFFRACTIONr_scbond_other4.0384.3847888
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.4786.36111376
X-RAY DIFFRACTIONr_long_range_B_refined8.1645.42817290
X-RAY DIFFRACTIONr_long_range_B_other8.16145.42917284
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A300980.08
12B300980.08
21A287840.07
22C287840.07
31A302280.07
32D302280.07
41B285180.07
42C285180.07
51B307280.07
52D307280.07
61C285820.07
62D285820.07
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 315 -
Rwork0.321 5996 -
obs--99.84 %

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