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- PDB-3r1g: Structure Basis of Allosteric Inhibition of BACE1 by an Exosite-B... -

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Basic information

Entry
Database: PDB / ID: 3r1g
TitleStructure Basis of Allosteric Inhibition of BACE1 by an Exosite-Binding Antibody
Components
  • Beta-secretase 1
  • FAB of YW412.8.31 antibody heavy chain
  • FAB of YW412.8.31 antibody light chain
KeywordsPROTEIN BINDING / Aspartal protease
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / multivesicular body / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / neuronal cell body / dendrite / Golgi apparatus / enzyme binding / cell surface / proteolysis / membrane / plasma membrane
Similarity search - Function
Beta-secretase BACE1 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Beta-secretase BACE1 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Immunoglobulins / Immunoglobulin-like / Beta Barrel / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsWang, W. / Rouge, L. / Wu, P. / Chiu, C. / Chen, Y. / Wu, Y. / Watts, R.J.
CitationJournal: Sci Transl Med / Year: 2011
Title: A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-{beta} Production in Vivo.
Authors: Atwal, J.K. / Chen, Y. / Chiu, C. / Mortensen, D.L. / Meilandt, W.J. / Liu, Y. / Heise, C.E. / Hoyte, K. / Luk, W. / Lu, Y. / Peng, K. / Wu, P. / Rouge, L. / Zhang, Y. / Lazarus, R.A. / ...Authors: Atwal, J.K. / Chen, Y. / Chiu, C. / Mortensen, D.L. / Meilandt, W.J. / Liu, Y. / Heise, C.E. / Hoyte, K. / Luk, W. / Lu, Y. / Peng, K. / Wu, P. / Rouge, L. / Zhang, Y. / Lazarus, R.A. / Scearce-Levie, K. / Wang, W. / Wu, Y. / Tessier-Lavigne, M. / Watts, R.J.
History
DepositionMar 10, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 8, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Beta-secretase 1
H: FAB of YW412.8.31 antibody heavy chain
L: FAB of YW412.8.31 antibody light chain


Theoretical massNumber of molelcules
Total (without water)91,2853
Polymers91,2853
Non-polymers00
Water1,71195
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5340 Å2
ΔGint-36 kcal/mol
Surface area33440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.112, 75.537, 112.016
Angle α, β, γ (deg.)90.00, 99.82, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Beta-secretase 1 / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta- ...Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 44643.145 Da / Num. of mol.: 1 / Fragment: Catalytic domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Antibody FAB of YW412.8.31 antibody heavy chain


Mass: 23282.092 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#3: Antibody FAB of YW412.8.31 antibody light chain


Mass: 23359.945 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / 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: 2.11 Å3/Da / Density % sol: 41.59 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1 ul of the BACE1/Fab complex solution mixed with 1 ul of well solution containing 20% PEG 4000, 0.1M Tris, 0.2 M sodium acetate, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.98057 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 10, 2009
RadiationMonochromator: side scattering I-beam bent single crystal, asymmetric cut 4.9650 deg
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98057 Å / Relative weight: 1
ReflectionResolution: 2.8→45 Å / Num. obs: 17490 / % possible obs: 97.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.5 % / Biso Wilson estimate: 55.69 Å2 / Rsym value: 0.112 / Net I/σ(I): 10.8
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 2.5 % / Mean I/σ(I) obs: 2 / Rsym value: 0.366 / % possible all: 84.4

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
PHENIX(phenix.refine: 1.6.4_486)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→44.791 Å / SU ML: 0.4 / σ(F): 1.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2683 939 5.1 %5% random
Rwork0.222 ---
obs0.2243 17490 97.84 %-
all-17876 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 31.481 Å2 / ksol: 0.333 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-6.7721 Å20 Å2-8.6864 Å2
2---5.4823 Å20 Å2
3----1.2899 Å2
Refinement stepCycle: LAST / Resolution: 2.8→44.791 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6237 0 0 95 6332
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.94750.30781080.26342194X-RAY DIFFRACTION86
2.9475-3.13210.27811450.23572487X-RAY DIFFRACTION98
3.1321-3.37390.26041270.21272548X-RAY DIFFRACTION100
3.3739-3.71320.28361550.1992515X-RAY DIFFRACTION100
3.7132-4.25020.2211230.20312595X-RAY DIFFRACTION100
4.2502-5.35340.24631290.19862539X-RAY DIFFRACTION100
5.3534-44.79640.3061520.2682609X-RAY DIFFRACTION100
Refinement TLS params.

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

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.14430.0931-0.08080.1503-0.17410.1807-0.0955-0.09710.12280.13880.06940.09180.00970.436100.15270.0001-0.01050.40460.00140.184638.594562.880149.2642
20.3069-0.041-0.01350.0098-0.1090.2877-0.2120.0644-0.04590.05230.08080.1056-0.03110.1574-0.05460.1361-0.0167-0.02380.0978-0.05050.114525.341250.849416.262
30.1997-0.02670.1010.21640.28420.3355-0.1714-0.21710.0618-0.14130.04950.0548-0.1371-0.12160.00020.21660.0839-0.07580.1267-0.0450.125216.865867.383452.3019
40.03860.0273-0.06460.0654-0.03970.12-0.0161-0.0928-0.1187-0.2262-0.03790.22440.028-0.04300.19050.06560.02320.1426-0.02540.229415.166249.358528.8807
50.44950.11250.01820.8363-0.32910.8744-0.00670.0561-0.01380.01910.0136-0.0118-0.0212-0.0120.00010.04920.0093-0.02680.0065-0.0240.074527.86651.699292.4359
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN L AND RESID 1:110
2X-RAY DIFFRACTION2CHAIN L AND RESID 111:214
3X-RAY DIFFRACTION3CHAIN H AND RESID 1:114
4X-RAY DIFFRACTION4CHAIN H AND RESID 115:218
5X-RAY DIFFRACTION5CHAIN B

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