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- PDB-9had: Der f 21 dust mite allergen with computationally designed DerF21_... -

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Basic information

Entry
Database: PDB / ID: 9had
TitleDer f 21 dust mite allergen with computationally designed DerF21_b10 binder
Components
  • DerF21_binder10
  • Mite allergen Der f 21.0101
KeywordsDE NOVO PROTEIN / dust mite / allergen / Der f 21 / computational / de novo / binder
Function / homologyMite allergen, group 5/21 / Mite allergen, group 5/21 superfamily / Mite allergen Blo t 5 / protein homodimerization activity / Mite allergen Der f 21.0101
Function and homology information
Biological speciesDermatophagoides farinae (American house dust mite)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsPacesa, M. / Nickel, L. / Correia, B.E.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: bioRxiv / Year: 2024
Title: BindCraft: one-shot design of functional protein binders.
Authors: Martin Pacesa / Lennart Nickel / Christian Schellhaas / Joseph Schmidt / Ekaterina Pyatova / Lucas Kissling / Patrick Barendse / Jagrity Choudhury / Srajan Kapoor / Ana Alcaraz-Serna / ...Authors: Martin Pacesa / Lennart Nickel / Christian Schellhaas / Joseph Schmidt / Ekaterina Pyatova / Lucas Kissling / Patrick Barendse / Jagrity Choudhury / Srajan Kapoor / Ana Alcaraz-Serna / Yehlin Cho / Kourosh H Ghamary / Laura Vinué / Brahm J Yachnin / Andrew M Wollacott / Stephen Buckley / Adrie H Westphal / Simon Lindhoud / Sandrine Georgeon / Casper A Goverde / Georgios N Hatzopoulos / Pierre Gönczy / Yannick D Muller / Gerald Schwank / Daan C Swarts / Alex J Vecchio / Bernard L Schneider / Sergey Ovchinnikov / Bruno E Correia
Abstract: Protein-protein interactions (PPIs) are at the core of all key biological processes. However, the complexity of the structural features that determine PPIs makes their design challenging. We present ...Protein-protein interactions (PPIs) are at the core of all key biological processes. However, the complexity of the structural features that determine PPIs makes their design challenging. We present BindCraft, an open-source and automated pipeline for protein binder design with experimental success rates of 10-100%. BindCraft leverages the weights of AlphaFold2 to generate binders with nanomolar affinity without the need for high-throughput screening or experimental optimization, even in the absence of known binding sites. We successfully designed binders against a diverse set of challenging targets, including cell-surface receptors, common allergens, designed proteins, and multi-domain nucleases, such as CRISPR-Cas9. We showcase the functional and therapeutic potential of designed binders by reducing IgE binding to birch allergen in patient-derived samples, modulating Cas9 gene editing activity, and reducing the cytotoxicity of a foodborne bacterial enterotoxin. Lastly, we utilize cell surface receptor-specific binders to redirect AAV capsids for targeted gene delivery. This work represents a significant advancement towards a "one design-one binder" approach in computational design, with immense potential in therapeutics, diagnostics, and biotechnology.
History
DepositionNov 3, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_CSD / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mite allergen Der f 21.0101
B: Mite allergen Der f 21.0101
C: DerF21_binder10
D: DerF21_binder10


Theoretical massNumber of molelcules
Total (without water)57,5624
Polymers57,5624
Non-polymers00
Water25214
1
A: Mite allergen Der f 21.0101
D: DerF21_binder10


Theoretical massNumber of molelcules
Total (without water)28,7812
Polymers28,7812
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mite allergen Der f 21.0101
C: DerF21_binder10


Theoretical massNumber of molelcules
Total (without water)28,7812
Polymers28,7812
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)52.580, 65.440, 72.225
Angle α, β, γ (deg.)90.000, 110.856, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 9 through 27 or resid 29...
d_2ens_1(chain "B" and (resid 9 through 27 or resid 29...
d_1ens_2(chain "C" and (resid 2 through 19 or resid 21...
d_2ens_2(chain "D" and (resid 2 through 19 or resid 21...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1LYSLYSASPASPAA9 - 279 - 27
d_12ens_1ILEILESERSERAA29 - 3729 - 37
d_13ens_1GLNGLNSERSERAA39 - 4839 - 48
d_14ens_1GLUGLULEULEUAA50 - 5650 - 56
d_15ens_1GLUGLUGLUGLUAA58 - 8658 - 86
d_16ens_1ASNASNVALVALAA89 - 10189 - 101
d_17ens_1ASPASPALAALAAA103 - 108103 - 108
d_18ens_1LYSLYSVALVALAA110 - 114110 - 114
d_19ens_1SERSERSERSERAA116116
d_21ens_1LYSLYSASPASPBB9 - 279 - 27
d_22ens_1ILEILESERSERBB29 - 3729 - 37
d_23ens_1GLNGLNSERSERBB39 - 4839 - 48
d_24ens_1GLUGLULEULEUBB50 - 5650 - 56
d_25ens_1GLUGLUGLUGLUBB58 - 8658 - 86
d_26ens_1ASNASNVALVALBB89 - 10189 - 101
d_27ens_1ASPASPALAALABB103 - 108103 - 108
d_28ens_1LYSLYSVALVALBB110 - 114110 - 114
d_29ens_1SERSERSERSERBB116116
d_11ens_2LEULEUGLUGLUCC2 - 192 - 19
d_12ens_2VALVALGLUGLUCC21 - 4521 - 45
d_13ens_2METMETGLUGLUCC47 - 7247 - 72
d_14ens_2SERSERGLUGLUCC74 - 9874 - 98
d_15ens_2LYSLYSGLYGLYCC100 - 109100 - 109
d_21ens_2LEULEUGLUGLUDD2 - 192 - 19
d_22ens_2VALVALGLUGLUDD21 - 4521 - 45
d_23ens_2METMETGLUGLUDD47 - 7247 - 72
d_24ens_2SERSERGLUGLUDD74 - 9874 - 98
d_25ens_2LYSLYSGLYGLYDD100 - 109100 - 109

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.996015892826, 0.0890717607576, -0.00430844213583), (0.0888503422465, -0.987096193544, 0.133216820908), (0.00761300996844, -0.133068877375, -0.991077552946)5.00059359253, 5.16034945611, -63.9887181822
2given(0.997738477321, 0.0575537258531, -0.0347203040475), (0.044770530545, -0.954328509074, -0.295385673931), (-0.0501351220946, 0.293163206098, -0.954746984349)-5.35476370149, -5.79856807341, -63.1618875138

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Components

#1: Protein Mite allergen Der f 21.0101 / Allergen Der f 21 / Mite group 21 allergen Der f 21


Mass: 14842.955 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Dermatophagoides farinae (American house dust mite)
Production host: Escherichia coli (E. coli) / References: UniProt: B2GM84
#2: Protein DerF21_binder10


Mass: 13938.052 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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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: 2.02 Å3/Da / Density % sol: 39.03 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, sitting drop / Details: 0.1 M Na citrate pH 5.6, 1.0 M LiSO4, 0.5 M NH4SO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9184 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Sep 21, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.75→46.98 Å / Num. obs: 15824 / % possible obs: 89.41 % / Redundancy: 2.2 % / Biso Wilson estimate: 67.55 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.05685 / Net I/σ(I): 6.7
Reflection shellResolution: 2.75→3.02 Å / Rmerge(I) obs: 1.995 / Mean I/σ(I) obs: 0.26 / Num. unique obs: 800 / CC1/2: 0.176 / % possible all: 87.65

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.75→46.98 Å / SU ML: 0.4686 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 31.2668
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2672 576 5.32 %
Rwork0.215 10253 -
obs0.2178 10829 89.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 82.93 Å2
Refinement stepCycle: LAST / Resolution: 2.75→46.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3715 0 0 14 3729
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00273756
X-RAY DIFFRACTIONf_angle_d0.52935012
X-RAY DIFFRACTIONf_chiral_restr0.0319559
X-RAY DIFFRACTIONf_plane_restr0.0043634
X-RAY DIFFRACTIONf_dihedral_angle_d13.87581522
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS1.00211346876
ens_2d_2CCX-RAY DIFFRACTIONTorsion NCS0.987729706756
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-3.020.38141440.30332484X-RAY DIFFRACTION87.86
3.02-3.460.33951300.26832656X-RAY DIFFRACTION92.07
3.46-4.360.26811640.20932569X-RAY DIFFRACTION90.44
4.36-46.980.21751380.18242544X-RAY DIFFRACTION87.33
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)
10.7549749781930.2695911716040.4336587340061.832124727480.4894371489660.3592167260020.296382899744-0.464964503783-0.6363806011731.488893433490.116857278909-1.44174922588-2.52705691261-0.1857569234420.01911834189111.019614078770.213197334579-0.003955231667020.8785110903070.1435830697841.294213584891.9966405642814.679997407-55.1717627361
22.555936065170.758830413371-1.105756056933.54367700757-2.270106732362.15757215483-0.0331780380445-0.0928267323980.286471296328-0.0428763610926-0.1052472027370.2652944936770.172599538187-0.6917714156740.001391723377060.466199018442-0.141046907914-0.04543093693370.596082006094-0.09879662606450.577007080907-20.58583680260.0749434545982-41.3146506356
34.165778979741.39674101198-0.6551350936872.91716772109-0.3743308601223.00436579718-1.186082004080.677047843395-0.106527695793-1.74369570850.319975458709-0.3760355198281.20737080016-0.780339627615-0.2081282255880.635464342602-0.0748271064588-0.06448117084140.503218000074-0.0477595137780.45813090304-15.2625235645-0.974822407798-50.4996880482
41.725338710221.49381624191-0.3095347376452.58422469182-1.10066390061.010758700250.03305828987430.214170135689-0.1429586436050.717556596652-0.287188506576-0.979742026906-0.3163053898730.361285166027-0.03995986740610.54917765010.0951960049503-0.08968285040590.6083356240160.01147566672410.531902953859-8.69111078795-4.19895580087-24.0774163215
51.362253280090.8928833131040.2220987382124.0103544157-0.6488434950421.36976632195-0.0666212931934-0.4095912631880.03638149679030.73669658496-0.0165880661389-0.13864619664-0.528343934079-0.506827096393-0.01131256044250.526665846154-0.00647615655598-0.01069065293220.483910538449-0.05266248291080.397737009437-13.7095828442-3.10475088157-16.3705452509
62.313469661015.433056138932.468249033341.99800342828-0.6099099852346.87259310091-0.00705916639649-0.7538099711531.11239034997-2.431299579820.2617217061471.188727226120.3230136123980.2695893060330.1398550290280.7151355475950.2734553142610.2244954151910.9037195846440.000353209357971.10702778415-31.657821248113.9017139583-27.9985648668
76.91203124221-1.920432477331.303206348093.1559454549-0.653988998650.224982203137-0.09169646845610.736688182970.1849471542320.03101882421430.3246370322690.225228159769-0.1561241901740.4000639188870.01068861735410.41275888628-0.1130679157480.0756211970940.4827418886830.04087585890680.41830387195110.4045410019-1.43654376069-10.5410625289
84.61777146581-0.238170381251.506284800410.36470177565-1.500074800365.560975898330.0295955616592.67050958562.24897861035-1.05047635785-0.477095725602-0.3325171664761.054934659491.718956422810.6468295612370.478936287311-0.188609544428-0.01331724676070.9914589410390.3844633010190.9041603853116.38434686321.1825153253-13.2162544843
90.122114410070.372907617079-0.1051334486890.8009104427460.5699103627030.8991683768980.0626284453279-0.1261653361460.155142317133-0.0177612346922-0.0659730241733-0.241756048606-0.03823441231860.890927384465-0.00392443742280.936246731079-0.1171087328270.0473290680310.774115373202-0.05983696110470.596907259087.221661583044.61776967961-54.5674212873
100.878274120618-0.07717054876870.5345294613541.34430070637-0.5953975695230.530786847653-0.3489551752470.7322602431840.218309698605-0.2154670133340.5798816528730.402997426799-0.01321243462960.0488974357179-0.001128761575230.598040888912-0.01502801057070.02257056772720.741363024172-0.02220556043240.675683749397-1.15418965705-2.07060029438-51.473023572
110.3094430203230.5194150277130.4980240531571.874215070460.5714676035120.865353805306-0.2894162315150.61647627051-0.5674286273770.4546771276940.300283710869-1.007172918971.984453189721.125641880450.1750411587050.9581266725360.2108098468390.2660173531230.872562212294-0.1478958607370.82606055993411.2539837152-9.5941763569-56.5351809563
120.769481244158-2.70029262779-0.05826801258449.397387997060.1785422680920.00761499195251-1.0076539691-1.07065762894-0.803324763612-0.8110488796420.4359179386522.51643216233-1.47428344514-0.42496779933-1.779006524681.224536375390.01918821865470.2336658013120.8778923016750.2841892801350.680206116178-2.45077938313-9.68108332924-43.8056093343
130.6275396034640.8510869402140.1992205032021.353281228151.014215373351.52234995828-0.190474082159-0.144860623316-0.595594286306-0.00551176106614-0.017025229982-0.831215271089-0.5738362532931.202540649760.0009556277389530.7820085711670.0522603304926-0.003840276094691.04817423101-0.09269684580061.0831063647815.6382426091-0.549399489247-53.3216048014
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 3 through 12 )AA3 - 123 - 12
22chain 'A' and (resid 13 through 78 )AA13 - 7813 - 78
33chain 'A' and (resid 79 through 116 )AA79 - 11679 - 116
44chain 'B' and (resid 7 through 46 )BB7 - 461 - 40
55chain 'B' and (resid 47 through 112 )BB47 - 11241 - 106
66chain 'B' and (resid 113 through 118 )BB113 - 118107 - 112
77chain 'C' and (resid 2 through 69 )CC2 - 691 - 68
88chain 'C' and (resid 70 through 109 )CC70 - 10969 - 108
99chain 'D' and (resid 2 through 31 )DD2 - 311 - 30
1010chain 'D' and (resid 32 through 54 )DD32 - 5431 - 53
1111chain 'D' and (resid 55 through 69 )DD55 - 6954 - 68
1212chain 'D' and (resid 70 through 78 )DD70 - 7869 - 77
1313chain 'D' and (resid 79 through 109 )DD79 - 10978 - 108

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