[English] 日本語
Yorodumi
- PDB-5nx8: Crystal structure of Neanderthal Adenylosuccinate Lyase (ADSL) -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 5nx8
TitleCrystal structure of Neanderthal Adenylosuccinate Lyase (ADSL)
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 / nucleotide binding / cytosol
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
DI(HYDROXYETHYL)ETHER / Adenylosuccinate lyase
Similarity search - Component
Biological speciesHomo sapiens neanderthalensis (Neandertal)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 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 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)222,36025
Polymers220,8664
Non-polymers1,49421
Water21,4561191
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: SAXS, SAXS and size exlusion chromatograhy confirm tetrameric structure in solution.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area34550 Å2
ΔGint-192 kcal/mol
Surface area63080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.390, 104.880, 215.400
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

-
Components

#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
#2: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H10O3
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1191 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.19 Å3/Da / Density % sol: 43.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 19-21% PEG6000, 0.1 M Tris pH 8

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.7→48 Å / Num. obs: 211102 / % possible obs: 99.5 % / Redundancy: 4.6 % / Biso Wilson estimate: 29 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.116 / Net I/σ(I): 9.8
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 4.7 % / Mean I/σ(I) obs: 1.2 / Num. unique obs: 30633 / CC1/2: 0.42 / Rrim(I) all: 1.3 / % possible all: 99.8

-
Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2J91

2j91


Resolution: 1.7→19.96 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.952 / Cross valid method: THROUGHOUT / ESU R: 0.102 / ESU R Free: 0.105 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21493 10542 5 %RANDOM
Rwork0.17126 ---
obs0.17343 200295 99.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 31.021 Å2
Baniso -1Baniso -2Baniso -3
1--0.85 Å2-0 Å2-0 Å2
2---0.93 Å20 Å2
3---1.78 Å2
Refinement stepCycle: 1 / Resolution: 1.7→19.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14636 0 86 1191 15913
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.01915088
X-RAY DIFFRACTIONr_bond_other_d00.0214664
X-RAY DIFFRACTIONr_angle_refined_deg1.4961.96720369
X-RAY DIFFRACTIONr_angle_other_deg3.558333718
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.22351856
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.06523.606710
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.965152763
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.12315134
X-RAY DIFFRACTIONr_chiral_restr0.0990.22297
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0216919
X-RAY DIFFRACTIONr_gen_planes_other0.0180.023483
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_it2.5322.8067388
X-RAY DIFFRACTIONr_mcbond_other2.5312.8067387
X-RAY DIFFRACTIONr_mcangle_it3.4364.1929244
X-RAY DIFFRACTIONr_mcangle_other3.4364.1929245
X-RAY DIFFRACTIONr_scbond_it3.853.2727700
X-RAY DIFFRACTIONr_scbond_other3.8493.2727700
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.784.72211122
X-RAY DIFFRACTIONr_long_range_B_refined7.20323.12718536
X-RAY DIFFRACTIONr_long_range_B_other7.20323.12918537
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 771 -
Rwork0.344 14657 -
obs--99.75 %

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more