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- PDB-37hf: PCSK9 bound to small molecule inhibitor AZD-0780 -

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Basic information

Entry
Database: PDB / ID: 37hf
TitlePCSK9 bound to small molecule inhibitor AZD-0780
Components
  • Propeptide of Proprotein convertase subtilisin/kexin type 9
  • Proprotein convertase subtilisin/kexin type 9
KeywordsPROTEIN BINDING / PCSK9 / AZD0780 / C-terminal domain / LDL receptor regulation
Function / homology
Function and homology information


low-density lipoprotein particle receptor catabolic process / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / extrinsic component of external side of plasma membrane / negative regulation of sodium ion import across plasma membrane / PCSK9-LDLR complex / PCSK9-AnxA2 complex / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding / positive regulation of low-density lipoprotein particle receptor catabolic process ...low-density lipoprotein particle receptor catabolic process / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / extrinsic component of external side of plasma membrane / negative regulation of sodium ion import across plasma membrane / PCSK9-LDLR complex / PCSK9-AnxA2 complex / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding / positive regulation of low-density lipoprotein particle receptor catabolic process / low-density lipoprotein particle binding / LDL clearance / very-low-density lipoprotein particle receptor binding / transporter inhibitor activity / signaling receptor inhibitor activity / negative regulation of receptor internalization / COPII-coated ER to Golgi transport vesicle / sodium channel inhibitor activity / endolysosome membrane / negative regulation of low-density lipoprotein particle clearance / lysosomal transport / low-density lipoprotein particle receptor binding / protein autoprocessing / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / positive regulation of receptor internalization / apolipoprotein binding / cholesterol metabolic process / neurogenesis / kidney development / cholesterol homeostasis / liver development / regulation of neuron apoptotic process / cellular response to starvation / VLDLR internalisation and degradation / Post-translational protein phosphorylation / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of neuron apoptotic process / cellular response to insulin stimulus / late endosome / neuron differentiation / endopeptidase activity / early endosome / lysosome / endoplasmic reticulum lumen / serine-type endopeptidase activity / lysosomal membrane / apoptotic process / perinuclear region of cytoplasm / Golgi apparatus / cell surface / endoplasmic reticulum / : / RNA binding / extracellular region / plasma membrane / cytoplasm
Similarity search - Function
Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proteinase K-like catalytic domain / Peptidase S8 propeptide/proteinase inhibitor I9 / Peptidase inhibitor I9 / Peptidase S8 propeptide/proteinase inhibitor I9 superfamily ...Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proteinase K-like catalytic domain / Peptidase S8 propeptide/proteinase inhibitor I9 / Peptidase inhibitor I9 / Peptidase S8 propeptide/proteinase inhibitor I9 superfamily / : / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain
Similarity search - Domain/homology
: / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.072 Å
AuthorsAbramyan, T. / Janczyk, P.L. / Papoian, G.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: Biorxiv / Year: 2026
Title: Overcoming the accuracy-generalization tradeoff in docking and scoring for prospective virtual screening
Authors: Petrosyan, G. / Altunyan, V. / Ghukasyan, T. / Abramyan, T.M. / Arakelov, G. / Davtyan, A. / Aghajanyan, T. / Nakipov, I. / Navasardyan, G. / Fahradyan, A. / Tunanyan, H. / Simonyan, A. / ...Authors: Petrosyan, G. / Altunyan, V. / Ghukasyan, T. / Abramyan, T.M. / Arakelov, G. / Davtyan, A. / Aghajanyan, T. / Nakipov, I. / Navasardyan, G. / Fahradyan, A. / Tunanyan, H. / Simonyan, A. / Janczyk, P.L. / De Silva, D. / Saribekyan, H. / Tsidilkovski, L. / Arakelov, V. / Ginoyan, N. / Mnatsakanyan, H. / Ratnikov, M. / Smbatyan, K. / Papoyan, A. / Papoian, G.A.
History
DepositionJul 21, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Propeptide of Proprotein convertase subtilisin/kexin type 9
B: Proprotein convertase subtilisin/kexin type 9
C: Propeptide of Proprotein convertase subtilisin/kexin type 9
D: Proprotein convertase subtilisin/kexin type 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)144,6237
Polymers144,1284
Non-polymers4953
Water9,080504
1
A: Propeptide of Proprotein convertase subtilisin/kexin type 9
B: Proprotein convertase subtilisin/kexin type 9
hetero molecules


  • defined by author&software
  • Evidence: homology, Assembly assignment is based on known PCSK9 domain organization and homologous PCSK9 crystal structures. The deposited asymmetric unit contains two PCSK9 prodomain:catalytic/CRD ...Evidence: homology, Assembly assignment is based on known PCSK9 domain organization and homologous PCSK9 crystal structures. The deposited asymmetric unit contains two PCSK9 prodomain:catalytic/CRD copies, but the biologically relevant ligand-bound copy is chains A and B.
  • 72.5 kDa, 2 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)72,5194
Polymers72,0642
Non-polymers4542
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2550 Å2
ΔGint-29 kcal/mol
Surface area23900 Å2
MethodPISA
2
C: Propeptide of Proprotein convertase subtilisin/kexin type 9
D: Proprotein convertase subtilisin/kexin type 9
hetero molecules


  • defined by author&software
  • Evidence: homology, Assembly assignment is based on known PCSK9 domain organization and homologous PCSK9 crystal structures. The deposited asymmetric unit contains two PCSK9 prodomain:catalytic/CRD ...Evidence: homology, Assembly assignment is based on known PCSK9 domain organization and homologous PCSK9 crystal structures. The deposited asymmetric unit contains two PCSK9 prodomain:catalytic/CRD copies, but the biologically relevant ligand-bound copy is chains A and B.
  • 72.1 kDa, 2 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)72,1043
Polymers72,0642
Non-polymers401
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2380 Å2
ΔGint-30 kcal/mol
Surface area22750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.990, 109.447, 122.602
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11B
21D

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: SER / End label comp-ID: SER / Auth seq-ID: 153 - 681 / Label seq-ID: 1 - 529

Dom-IDAuth asym-IDLabel asym-ID
1BB
2DD

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Components

#1: Protein Propeptide of Proprotein convertase subtilisin/kexin type 9


Mass: 13791.463 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: PCSK9 Prodomain / Source: (gene. exp.) Homo sapiens (human) / Gene: PCSK9, NARC1, PSEC0052 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Protein Proprotein convertase subtilisin/kexin type 9 / Neural apoptosis-regulated convertase 1 / NARC-1 / Proprotein convertase 9 / PC9 / Subtilisin/kexin- ...Neural apoptosis-regulated convertase 1 / NARC-1 / Proprotein convertase 9 / PC9 / Subtilisin/kexin-like protease PC9


Mass: 58272.621 Da / Num. of mol.: 2 / Mutation: V474I, G670E
Source method: isolated from a genetically manipulated source
Details: PCSK9 Catalytic domain / Source: (gene. exp.) Homo sapiens (human) / Gene: PCSK9, NARC1, PSEC0052 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-A1IYR / 1-[6-[[(1~{S},3~{S})-3-[[5-[bis(fluoranyl)methoxy]pyrimidin-2-yl]amino]cyclopentyl]amino]pyridin-3-yl]pyridin-2-one


Mass: 414.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20F2N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 504 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.49 Å3/Da / Density % sol: 50.61 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 0.10 M MD - Buffer System 1, pH 5.80, 13.00 % MD - Precipitant Mix 2, 2.50 % (v/v) MD - Cryopolyols , 90.00 mM MD - LiNaK Mix

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.91508 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Oct 17, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91508 Å / Relative weight: 1
ReflectionResolution: 2.07→109.45 Å / Num. obs: 35755 / % possible obs: 40.6 % / Redundancy: 11.5 % / CC1/2: 0.98 / Rmerge(I) obs: 0.54 / Rpim(I) all: 0.24 / Rrim(I) all: 0.59 / Net I/σ(I): 4.2
Reflection shellResolution: 2.07→2.45 Å / Redundancy: 11.2 % / Rmerge(I) obs: 1.67 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1788 / CC1/2: 0.77 / Rpim(I) all: 0.74 / Rrim(I) all: 1.83 / % possible all: 5.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0431refinement
autoPROCdata reduction
SCALAdata scaling
STARANISOdata scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QTW

2qtw


Resolution: 2.072→109.447 Å / Cor.coef. Fo:Fc: 0.81 / Cor.coef. Fo:Fc free: 0.679 / SU B: 15.526 / SU ML: 0.222 / Cross valid method: THROUGHOUT / ESU R Free: 0.125
Details: Restrained maximum-likelihood refinement was performed in REFMAC using individual isotropic B factors, TLS refinement, local NCS restraints, Babinet bulk-solvent correction, and riding ...Details: Restrained maximum-likelihood refinement was performed in REFMAC using individual isotropic B factors, TLS refinement, local NCS restraints, Babinet bulk-solvent correction, and riding hydrogens. TLS groups were defined per protein chain. Ligand restraints for AZD0780 were generated with ACEDRG.
RfactorNum. reflection% reflectionSelection details
Rfree0.405 1829 5.115 %RANDOM
Rwork0.3273 33926 --
all0.331 ---
obs0.331 35755 40.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK / Bsol: 67.7315 Å2 / ksol: 0.7744 e/Å3
Displacement parametersBiso mean: 35.888 Å2
Baniso -1Baniso -2Baniso -3
1-6.334 Å20 Å20 Å2
2---10.818 Å20 Å2
3---4.484 Å2
Refinement stepCycle: LAST / Resolution: 2.072→109.447 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8277 0 32 504 8813
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0128519
X-RAY DIFFRACTIONr_bond_other_d0.0010.0168037
X-RAY DIFFRACTIONr_angle_refined_deg0.8021.81711569
X-RAY DIFFRACTIONr_angle_other_deg0.3171.74818483
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.06651089
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.149576
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.273101335
X-RAY DIFFRACTIONr_dihedral_angle_6_deg9.1510348
X-RAY DIFFRACTIONr_chiral_restr0.0370.21329
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.0210133
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021912
X-RAY DIFFRACTIONr_nbd_refined0.160.21595
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1820.28174
X-RAY DIFFRACTIONr_nbtor_refined0.160.24030
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.080.24426
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1390.2405
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2350.250
X-RAY DIFFRACTIONr_nbd_other0.190.2136
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2250.215
X-RAY DIFFRACTIONr_mcbond_it1.0012.3294410
X-RAY DIFFRACTIONr_mcbond_other1.0012.3294410
X-RAY DIFFRACTIONr_mcangle_it1.7734.1795468
X-RAY DIFFRACTIONr_mcangle_other1.7734.185469
X-RAY DIFFRACTIONr_scbond_it0.7662.3764109
X-RAY DIFFRACTIONr_scbond_other0.7662.3764110
X-RAY DIFFRACTIONr_scangle_it1.3854.3756098
X-RAY DIFFRACTIONr_scangle_other1.3854.3766099
X-RAY DIFFRACTIONr_lrange_it4.01724.2539015
X-RAY DIFFRACTIONr_lrange_other3.93924.2628980
X-RAY DIFFRACTIONr_ncsr_local_group_10.0650.0513719
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11BX-RAY DIFFRACTIONLocal ncs0.065310.0501
12DX-RAY DIFFRACTIONLocal ncs0.065310.0501
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.072-2.1250.13730.31162X-RAY DIFFRACTION1.0131
2.125-2.1840.42280.369118X-RAY DIFFRACTION1.9981
2.184-2.2470.35190.37201X-RAY DIFFRACTION3.4579
2.247-2.3160.412190.338338X-RAY DIFFRACTION6.003
2.316-2.3920.356380.35527X-RAY DIFFRACTION9.7835
2.392-2.4760.433500.348716X-RAY DIFFRACTION13.8018
2.476-2.5690.409540.36894X-RAY DIFFRACTION17.68
2.569-2.6740.432560.3471340X-RAY DIFFRACTION26.7024
2.674-2.7930.398940.3361744X-RAY DIFFRACTION37.1163
2.793-2.9290.4181040.3192154X-RAY DIFFRACTION47.3276
2.929-3.0880.3811130.3212511X-RAY DIFFRACTION57.8866
3.088-3.2750.4021500.3192743X-RAY DIFFRACTION67.2009
3.275-3.5010.3621660.3033107X-RAY DIFFRACTION80.4177
3.501-3.7810.4161510.2993341X-RAY DIFFRACTION92.4543
3.781-4.1410.3921750.2993317X-RAY DIFFRACTION99.7144
4.141-4.6290.391870.32993X-RAY DIFFRACTION100
4.629-5.3440.4061450.3412685X-RAY DIFFRACTION100
5.344-6.5410.4581310.3842282X-RAY DIFFRACTION99.8758
6.541-9.2340.431280.3821776X-RAY DIFFRACTION100
9.234-109.4470.475480.451077X-RAY DIFFRACTION99.8225
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)
12.89260.73121.07450.80530.67011.64930.0170.1075-0.321-0.166-0.0318-0.00530.131-0.04020.01480.10240.0016-0.00430.0787-0.02940.1042-10.38139.06131.048
20.7579-0.1865-0.820.45060.65851.79920.00560.0237-0.0138-0.0599-0.00340.0228-0.0838-0.003-0.00220.01-0.006-0.00320.0890.01740.009517.76152.87124.847
30.6497-0.4585-1.16710.60630.69782.47040.1050.23970.26510.11460.0471-0.42960.047-0.4459-0.15210.20760.0553-0.04020.32910.04070.403355.08616.36412.066
40.628-0.17290.79410.4093-0.37371.0958-0.03270.0009-0.0553-0.01050.0144-0.0069-0.04930.01290.01830.1501-0.00740.01150.23320.00560.285727.32.5112.198
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLA62
2X-RAY DIFFRACTION1ALLB63 - 65
3X-RAY DIFFRACTION1ALLC66
4X-RAY DIFFRACTION1ALLD67 - 68
5X-RAY DIFFRACTION1ALLW69
6X-RAY DIFFRACTION1ALLA70 - 152
7X-RAY DIFFRACTION2ALLB153 - 2001
8X-RAY DIFFRACTION3ALLC62 - 152
9X-RAY DIFFRACTION4ALLD153 - 1501

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