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- PDB-7jy3: Structure of HbA with compound 23 (PF-07059013) -

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ID or keywords:

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Basic information

Entry
Database: PDB / ID: 7jy3
TitleStructure of HbA with compound 23 (PF-07059013)
Components(Hemoglobin subunit ...) x 2
KeywordsOXYGEN TRANSPORT / hemoglobin
Function / homology
Function and homology information


cellular oxidant detoxification / nitric oxide transport / hemoglobin alpha binding / haptoglobin-hemoglobin complex / organic acid binding / hemoglobin binding / renal absorption / hemoglobin complex / oxygen transport / Scavenging of heme from plasma ...cellular oxidant detoxification / nitric oxide transport / hemoglobin alpha binding / haptoglobin-hemoglobin complex / organic acid binding / hemoglobin binding / renal absorption / hemoglobin complex / oxygen transport / Scavenging of heme from plasma / endocytic vesicle lumen / blood vessel diameter maintenance / hydrogen peroxide catabolic process / oxygen carrier activity / Late endosomal microautophagy / Heme signaling / carbon dioxide transport / Erythrocytes take up oxygen and release carbon dioxide / response to hydrogen peroxide / Erythrocytes take up carbon dioxide and release oxygen / Cytoprotection by HMOX1 / platelet aggregation / oxygen binding / regulation of blood pressure / Chaperone Mediated Autophagy / positive regulation of nitric oxide biosynthetic process / tertiary granule lumen / Factors involved in megakaryocyte development and platelet production / ficolin-1-rich granule lumen / blood microparticle / iron ion binding / heme binding / Neutrophil degranulation / extracellular space / extracellular exosome / extracellular region / membrane / metal ion binding / cytosol
Similarity search - Function
Hemoglobin, pi / Hemoglobin, alpha-type / Hemoglobin, beta-type / Globin/Protoglobin / Globin domain profile. / Globin / Globin / Globin-like superfamily
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / 1,4,7,10,13,16-HEXAOXACYCLOOCTADECANE / OXYGEN MOLECULE / Chem-VUD / Hemoglobin subunit beta / Hemoglobin subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.48 Å
AuthorsJasti, J.
CitationJournal: J.Med.Chem. / Year: 2021
Title: PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.
Authors: Gopalsamy, A. / Aulabaugh, A.E. / Barakat, A. / Beaumont, K.C. / Cabral, S. / Canterbury, D.P. / Casimiro-Garcia, A. / Chang, J.S. / Chen, M.Z. / Choi, C. / Dow, R.L. / Fadeyi, O.O. / Feng, ...Authors: Gopalsamy, A. / Aulabaugh, A.E. / Barakat, A. / Beaumont, K.C. / Cabral, S. / Canterbury, D.P. / Casimiro-Garcia, A. / Chang, J.S. / Chen, M.Z. / Choi, C. / Dow, R.L. / Fadeyi, O.O. / Feng, X. / France, S.P. / Howard, R.M. / Janz, J.M. / Jasti, J. / Jasuja, R. / Jones, L.H. / King-Ahmad, A. / Knee, K.M. / Kohrt, J.T. / Limberakis, C. / Liras, S. / Martinez, C.A. / McClure, K.F. / Narayanan, A. / Narula, J. / Novak, J.J. / O'Connell, T.N. / Parikh, M.D. / Piotrowski, D.W. / Plotnikova, O. / Robinson, R.P. / Sahasrabudhe, P.V. / Sharma, R. / Thuma, B.A. / Vasa, D. / Wei, L. / Wenzel, A.Z. / Withka, J.M. / Xiao, J. / Yayla, H.G.
History
DepositionAug 28, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hemoglobin subunit alpha
B: Hemoglobin subunit beta
C: Hemoglobin subunit alpha
D: Hemoglobin subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,72719
Polymers62,0814
Non-polymers4,64615
Water7,062392
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12380 Å2
ΔGint-108 kcal/mol
Surface area23990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.770, 82.470, 65.080
Angle α, β, γ (deg.)90.000, 99.540, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Hemoglobin subunit ... , 2 types, 4 molecules ACBD

#1: Protein Hemoglobin subunit alpha / / Alpha-globin / Hemoglobin alpha chain


Mass: 15150.353 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HBA1, HBA2 / Production host: Homo sapiens (human) / References: UniProt: P69905
#2: Protein Hemoglobin subunit beta / / Beta-globin / Hemoglobin beta chain


Mass: 15890.198 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HBB / Production host: Homo sapiens (human) / References: UniProt: P68871

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Non-polymers , 5 types, 407 molecules

#3: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Chemical
ChemComp-OXY / OXYGEN MOLECULE / Oxygen


Mass: 31.999 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: O2
#5: Chemical
ChemComp-O4B / 1,4,7,10,13,16-HEXAOXACYCLOOCTADECANE / 18-Crown-6


Mass: 264.315 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C12H24O6
#6: Chemical ChemComp-VUD / 6-{(1S)-1-[(2-amino-6-fluoroquinolin-3-yl)oxy]ethyl}-5-(1H-pyrazol-1-yl)pyridin-2(1H)-one


Mass: 365.361 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H16FN5O2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 392 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.26 Å3/Da / Density % sol: 45.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Tris-HCl, pH 8.0, 0.2 M lithium sulfate, 30-32% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.48→44.68 Å / Num. obs: 55793 / % possible obs: 96.1 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.061 / Net I/av σ(I): 11.3 / Net I/σ(I): 11.3
Reflection shellResolution: 1.48→1.49 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.604 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 496 / % possible all: 97.6

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
Aimless0.5.21data scaling
PDB_EXTRACT3.25data extraction
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3WHM

3whm


Resolution: 1.48→29.69 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.939 / SU R Cruickshank DPI: 0.12 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.122 / SU Rfree Blow DPI: 0.112 / SU Rfree Cruickshank DPI: 0.111
RfactorNum. reflection% reflectionSelection details
Rfree0.207 2775 4.97 %RANDOM
Rwork0.18 ---
obs0.181 55793 60.5 %-
Displacement parametersBiso max: 106.1 Å2 / Biso mean: 26.28 Å2 / Biso min: 8.16 Å2
Baniso -1Baniso -2Baniso -3
1--2.4548 Å20 Å20.6565 Å2
2--0.297 Å20 Å2
3---2.1578 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.48→29.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4384 0 324 392 5100
Biso mean--23.83 37.13 -
Num. residues----574
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1577SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes886HARMONIC5
X-RAY DIFFRACTIONt_it4872HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion570SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5872SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4872HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6653HARMONIC20.93
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion16.85
LS refinement shellResolution: 1.48→1.49 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2087 5 6.67 %
Rwork-70 -
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)
12.96410.0620.12310.8834-0.13880.6371-0.09130.4946-0.5297-0.12650.0681-0.06280.05190.0510.0232-0.1497-0.03570.0347-0.0782-0.1545-0.067814.5781-11.824431.2918
23.2134-0.0531-0.05230.99820.10170.4266-0.07260.44670.1571-0.00910.07450.0499-0.07-0.0245-0.0018-0.1194-0.0307-0.0106-0.05410.0181-0.1278-2.47835.52630.8483
31.71690.03490.15070.4408-0.12310.3123-0.01-0.2598-0.29310.05540.00350.03350.0125-0.0780.0065-0.17150.00140.0128-0.14160.059-0.086-0.1483-10.966458.2574
42.56190.36450.26331.26950.17740.8808-0.0405-0.11760.1922-0.0687-0.01340.0522-0.0741-0.00450.0539-0.18490.0019-0.0012-0.1864-0.0227-0.15116.95046.536157.4769
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 141
2X-RAY DIFFRACTION2{ B|* }B1 - 146
3X-RAY DIFFRACTION3{ C|* }C1 - 141
4X-RAY DIFFRACTION4{ D|* }D1 - 146

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