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

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Basic information

Entry
Database: PDB / ID: 5nxa
TitleCrystal structure of Neanderthal Adenylosuccinate Lyase (ADSL)in complex with its products AICAR 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
AMINOIMIDAZOLE 4-CARBOXAMIDE RIBONUCLEOTIDE / FUMARIC ACID / Chem-SSS / Adenylosuccinate lyase
Similarity search - Component
Biological speciesHomo sapiens neanderthalensis (Neandertal)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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
E: Adenylosuccinate lyase
F: Adenylosuccinate lyase
G: Adenylosuccinate lyase
H: Adenylosuccinate lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)445,64926
Polymers441,7328
Non-polymers3,91818
Water6,503361
1
A: Adenylosuccinate lyase
B: Adenylosuccinate lyase
C: Adenylosuccinate lyase
D: Adenylosuccinate lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)222,82513
Polymers220,8664
Non-polymers1,9599
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area35760 Å2
ΔGint-165 kcal/mol
Surface area57410 Å2
MethodPISA
2
E: Adenylosuccinate lyase
F: Adenylosuccinate lyase
G: Adenylosuccinate lyase
H: Adenylosuccinate lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)222,82513
Polymers220,8664
Non-polymers1,9599
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area39470 Å2
ΔGint-181 kcal/mol
Surface area58990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)356.530, 74.210, 160.310
Angle α, β, γ (deg.)90.00, 108.99, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14A
24E
15A
25F
16A
26G
17A
27H
18B
28D
19B
29E
110B
210F
111B
211G
112B
212H
113C
213D
114C
214E
115C
215F
116C
216G
117C
217H
118D
218E
119D
219F
120D
220G
121D
221H
122E
222F
123E
223G
124E
224H
125F
225G
126F
226H
127G
227H

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
11GLUGLUCYSCYSAA70 - 48373 - 486
21GLYGLYCYSCYSBB8 - 48311 - 486
12SERSERLEULEUAA9 - 48212 - 485
22SERSERLEULEUCC9 - 48212 - 485
13GLYGLYLEULEUAA8 - 48411 - 487
23GLYGLYLEULEUDD8 - 48411 - 487
14GLYGLYLEULEUAA8 - 48411 - 487
24GLYGLYLEULEUEE8 - 48411 - 487
15GLYGLYLEULEUAA8 - 48411 - 487
25GLYGLYLEULEUFF8 - 48411 - 487
16SERSERCYSCYSAA9 - 48312 - 486
26SERSERCYSCYSGG9 - 48312 - 486
17GLYGLYLEULEUAA8 - 48411 - 487
27GLYGLYLEULEUHH8 - 48411 - 487
18GLYGLYCYSCYSBB8 - 48311 - 486
28GLUGLUCYSCYSDD70 - 48373 - 486
19GLYGLYCYSCYSBB8 - 48311 - 486
29GLUGLUCYSCYSEE70 - 48373 - 486
110GLYGLYCYSCYSBB8 - 48311 - 486
210GLUGLUCYSCYSFF70 - 48373 - 486
111GLYGLYCYSCYSBB8 - 48311 - 486
211GLUGLUCYSCYSGG70 - 48373 - 486
112GLYGLYCYSCYSBB8 - 48311 - 486
212GLUGLUCYSCYSHH70 - 48373 - 486
113SERSERLEULEUCC9 - 48212 - 485
213SERSERLEULEUDD9 - 48212 - 485
114SERSERLEULEUCC9 - 48212 - 485
214SERSERLEULEUEE9 - 48212 - 485
115SERSERLEULEUCC9 - 48212 - 485
215SERSERLEULEUFF9 - 48212 - 485
116SERSERLEULEUCC9 - 48212 - 485
216SERSERLEULEUGG9 - 48212 - 485
117SERSERLEULEUCC9 - 48212 - 485
217SERSERLEULEUHH9 - 48212 - 485
118GLYGLYLEULEUDD8 - 48411 - 487
218GLYGLYLEULEUEE8 - 48411 - 487
119GLYGLYLEULEUDD8 - 48411 - 487
219GLYGLYLEULEUFF8 - 48411 - 487
120SERSERLEULEUDD9 - 48412 - 487
220SERSERLEULEUGG9 - 48412 - 487
121GLYGLYLEULEUDD8 - 48411 - 487
221GLYGLYLEULEUHH8 - 48411 - 487
122GLYGLYLEULEUEE8 - 48411 - 487
222GLYGLYLEULEUFF8 - 48411 - 487
123SERSERLEULEUEE9 - 48412 - 487
223SERSERLEULEUGG9 - 48412 - 487
124GLYGLYLEULEUEE8 - 48411 - 487
224GLYGLYLEULEUHH8 - 48411 - 487
125SERSERLEULEUFF9 - 48412 - 487
225SERSERLEULEUGG9 - 48412 - 487
126GLYGLYLEULEUFF8 - 48411 - 487
226GLYGLYLEULEUHH8 - 48411 - 487
127SERSERLEULEUGG9 - 48412 - 487
227SERSERLEULEUHH9 - 48412 - 487

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27

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Components

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Protein , 1 types, 8 molecules ABCDEFGH

#1: Protein
Adenylosuccinate lyase / / ASL / Adenylosuccinase / ASase


Mass: 55216.445 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens neanderthalensis (Neandertal)
Gene: ADSL, AMPS / 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 , 5 types, 379 molecules

#2: Chemical
ChemComp-SSS / N-{[5-AMINO-1-(5-O-PHOSPHONO-BETA-D-ARABINOFURANOSYL)-1H-IMIDAZOL-4-YL]CARBONYL}-L-ASPARTIC ACID / N-{[5-AMINO-1-(5-O-PHOSPHONO-BETA-D-ARABINOFURANOSYL)-1H-IMIDAZOL-4-YL]CARBONYL}-L-ASPARTIC ACID


Mass: 454.283 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C13H19N4O12P
#3: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Cl
#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-AMZ / AMINOIMIDAZOLE 4-CARBOXAMIDE RIBONUCLEOTIDE / AICAR / AICA ribonucleotide


Mass: 338.211 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N4O8P
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 361 / 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: 2.25 Å3/Da / Density % sol: 45.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20 % ethylene glycol, 10 % PEG8000, 0.1 M imidazole/MES pH 6.5, 0.12 M alcohols (Morpheus screen Molecular Dimensions)

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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: Apr 7, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.967 Å / Relative weight: 1
ReflectionResolution: 2.4→49 Å / Num. obs: 153910 / % possible obs: 99 % / Redundancy: 4.5 % / Biso Wilson estimate: 42 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.22 / Net I/σ(I): 6.8
Reflection shellResolution: 2.4→2.5 Å / Redundancy: 4.6 % / Num. unique obs: 22475 / CC1/2: 0.45 / Rrim(I) all: 1.39 / % possible all: 99.9

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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: 2.4→47.85 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.921 / Cross valid method: THROUGHOUT / ESU R: 0.549 / ESU R Free: 0.28 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25428 7694 5 %RANDOM
Rwork0.22027 ---
obs0.22198 146181 98.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.07 Å2
Baniso -1Baniso -2Baniso -3
1-0.37 Å20 Å21.68 Å2
2---2.39 Å20 Å2
3---0.7 Å2
Refinement stepCycle: 1 / Resolution: 2.4→47.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms28814 0 248 361 29423
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01929572
X-RAY DIFFRACTIONr_bond_other_d00.0227952
X-RAY DIFFRACTIONr_angle_refined_deg1.3721.97639939
X-RAY DIFFRACTIONr_angle_other_deg3.613364750
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.81453591
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.51123.5591374
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.47155439
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.13115265
X-RAY DIFFRACTIONr_chiral_restr0.0790.24524
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02132409
X-RAY DIFFRACTIONr_gen_planes_other0.0110.026062
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_it3.35.08514420
X-RAY DIFFRACTIONr_mcbond_other3.2995.08514418
X-RAY DIFFRACTIONr_mcangle_it4.897.62717993
X-RAY DIFFRACTIONr_mcangle_other4.897.62717993
X-RAY DIFFRACTIONr_scbond_it3.835.46915152
X-RAY DIFFRACTIONr_scbond_other3.835.46815153
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.9358.04121947
X-RAY DIFFRACTIONr_long_range_B_refined7.75159.88733067
X-RAY DIFFRACTIONr_long_range_B_other7.75159.88733064
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)
11A241000.09
12B241000.09
21A271480.07
22C271480.07
31A282480.07
32D282480.07
41A294980.07
42E294980.07
51A299820.07
52F299820.07
61A301460.07
62G301460.07
71A301740.06
72H301740.06
81B224300.1
82D224300.1
91B243180.09
92E243180.09
101B242280.1
102F242280.1
111B238540.09
112G238540.09
121B252580.08
122H252580.08
131C266200.09
132D266200.09
141C271840.07
142E271840.07
151C269540.08
152F269540.08
161C271600.07
162G271600.07
171C272880.07
172H272880.07
181D283720.09
182E283720.09
191D282420.08
192F282420.08
201D283260.08
202G283260.08
211D285040.08
212H285040.08
221E293240.08
222F293240.08
231E290920.08
232G290920.08
241E304200.07
242H304200.07
251F300640.08
252G300640.08
261F300800.08
262H300800.08
271G299160.07
272H299160.07
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.372 568 -
Rwork0.376 10805 -
obs--99.75 %

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