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Entry
Database: PDB / ID: 6zis
TitleCrystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor
ComponentsMaltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor
KeywordsMEMBRANE PROTEIN / GPCR / CGRP / CLR / RAMP1 / ECD / COMPLEX
Function / homology
Function and homology information


calcitonin gene-related peptide binding / cellular response to sucrose stimulus / adrenomedullin binding / CGRP receptor complex / : / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity / calcitonin receptor activity ...calcitonin gene-related peptide binding / cellular response to sucrose stimulus / adrenomedullin binding / CGRP receptor complex / : / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity / calcitonin receptor activity / calcitonin gene-related peptide receptor signaling pathway / vascular associated smooth muscle cell proliferation / calcitonin gene-related peptide receptor activity / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / Calcitonin-like ligand receptors / regulation of G protein-coupled receptor signaling pathway / cell envelope / detection of maltose stimulus / maltose transport complex / carbohydrate transport / carbohydrate transmembrane transporter activity / maltose binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / maltose transport / maltodextrin transmembrane transport / cellular response to hormone stimulus / coreceptor activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / positive regulation of vascular associated smooth muscle cell proliferation / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / protein localization to plasma membrane / intracellular protein transport / G protein-coupled receptor activity / receptor internalization / adenylate cyclase-activating G protein-coupled receptor signaling pathway / calcium ion transport / protein transport / outer membrane-bounded periplasmic space / heart development / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / angiogenesis / G alpha (s) signalling events / periplasmic space / cell surface receptor signaling pathway / lysosome / receptor complex / endosome / G protein-coupled receptor signaling pathway / DNA damage response / cell surface / endoplasmic reticulum / metal ion binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
GPCR, family 2, calcitonin gene-related peptide, type 1 receptor / Receptor activity modifying protein / RAMP domain superfamily / Receptor activity modifying family / GPCR, family 2, calcitonin receptor family / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors ...GPCR, family 2, calcitonin gene-related peptide, type 1 receptor / Receptor activity modifying protein / RAMP domain superfamily / Receptor activity modifying family / GPCR, family 2, calcitonin receptor family / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain
Similarity search - Domain/homology
alpha-maltose / Chem-3N6 / Maltodextrin-binding protein / Receptor activity-modifying protein 1 / Maltose/maltodextrin-binding periplasmic protein / Calcitonin gene-related peptide type 1 receptor
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.73 Å
AuthorsSouthall, S.M.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structure-Based Drug Discovery ofN-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2'-oxo-1',2'- ...Title: Structure-Based Drug Discovery ofN-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine.
Authors: Bucknell, S.J. / Ator, M.A. / Brown, A.J.H. / Brown, J. / Cansfield, A.D. / Cansfield, J.E. / Christopher, J.A. / Congreve, M. / Cseke, G. / Deflorian, F. / Jones, C.R. / Mason, J.S. / ...Authors: Bucknell, S.J. / Ator, M.A. / Brown, A.J.H. / Brown, J. / Cansfield, A.D. / Cansfield, J.E. / Christopher, J.A. / Congreve, M. / Cseke, G. / Deflorian, F. / Jones, C.R. / Mason, J.S. / O'Brien, M.A. / Ott, G.R. / Pickworth, M. / Southall, S.M.
History
DepositionJun 26, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 15, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / entity / entity_name_com / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_molecule_features / pdbx_nonpoly_scheme / struct_asym / struct_conn / struct_conn_type / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.occupancy / _atom_site.type_symbol / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_auth_comp_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _atom_site_anisotrop.pdbx_label_atom_id / _atom_site_anisotrop.pdbx_label_comp_id / _atom_site_anisotrop.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _struct_asym.entity_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Aug 5, 2020Group: Database references / Structure summary / Category: chem_comp / citation / citation_author
Item: _chem_comp.pdbx_synonyms / _citation.journal_volume ..._chem_comp.pdbx_synonyms / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 3.0Aug 18, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / database_2 / entity / entity_name_com / entity_src_gen / pdbx_nonpoly_scheme / pdbx_validate_close_contact / struct_conn / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_seq_id / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_seq_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _entity_name_com.name / _entity_src_gen.gene_src_strain / _entity_src_gen.pdbx_beg_seq_num / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_nonpoly_scheme.pdb_seq_num / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_value_order / _struct_ref.db_code / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.seq_align_beg / _struct_ref_seq.seq_align_end
Revision 4.0Aug 25, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_residues / struct_ref_seq / struct_ref_seq_dif
Item: _atom_site.auth_seq_id / _atom_site_anisotrop.pdbx_auth_seq_id ..._atom_site.auth_seq_id / _atom_site_anisotrop.pdbx_auth_seq_id / _pdbx_poly_seq_scheme.pdb_seq_num / _pdbx_unobs_or_zero_occ_residues.auth_seq_id / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq_dif.pdbx_auth_seq_num
Revision 4.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 4.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,1556
Polymers66,3611
Non-polymers1,7955
Water5,080282
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint14 kcal/mol
Surface area24530 Å2
Unit cell
Length a, b, c (Å)71.140, 76.980, 98.260
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Maltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Calcitonin-receptor-like ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Calcitonin-receptor-like receptor activity-modifying protein 1 / CRLR activity-modifying protein 1 / CGRP type 1 receptor / Calcitonin receptor-like receptor


Mass: 66360.555 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (strain K12) (bacteria), (gene. exp.) Homo sapiens (human)
Strain: K12 / Gene: malE, b4034, JW3994, RAMP1, CALCRL, CGRPR / Production host: Homo sapiens (human) / Strain (production host): HEK293 GNTI
References: UniProt: P0AEX9, UniProt: O60894, UniProt: Q16602, UniProt: A0A4P1LXE0*PLUS
#2: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose / alpha-maltose


Type: oligosaccharide, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: alpha-maltose
DescriptorTypeProgram
DGlcpa1-4DGlcpa1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1a_1-5]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp]{[(4+1)][a-D-Glcp]{}}LINUCSPDB-CARE
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-3N6 / N-{(1S)-5-amino-1-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]pentyl}-3,5-dibromo-Nalpha-{[4-(2-oxo-1,4-dihydroquinazolin-3 (2H)-yl)piperidin-1-yl]carbonyl}-D-tyrosinamide / Olcegepant


Mass: 869.645 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H47Br2N9O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 282 / 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: 2.13 Å3/Da / Density % sol: 42.28 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 0.1 M BIS-TRIS pH 5.5, 0.1 M ammonium acetate, 15 % PEG 10,000

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Data collection

DiffractionMean temperature: 88 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96861 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 13, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 1.73→76.98 Å / Num. obs: 57024 / % possible obs: 100 % / Redundancy: 7.6 % / Biso Wilson estimate: 27.75 Å2 / CC1/2: 0.992 / Net I/σ(I): 6.3
Reflection shellResolution: 1.73→1.77 Å / Redundancy: 7.8 % / Num. unique obs: 4154 / CC1/2: 0.427 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RWG

4rwg


Resolution: 1.73→57.62 Å / SU ML: 0.2573 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.1794
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2444 2718 4.77 %
Rwork0.1991 54227 -
obs0.2013 56945 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 35.4 Å2
Refinement stepCycle: LAST / Resolution: 1.73→57.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4496 0 116 282 4894
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00764750
X-RAY DIFFRACTIONf_angle_d0.89536448
X-RAY DIFFRACTIONf_chiral_restr0.0511686
X-RAY DIFFRACTIONf_plane_restr0.0053828
X-RAY DIFFRACTIONf_dihedral_angle_d20.13111774
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.73-1.760.33731470.32282778X-RAY DIFFRACTION99.97
1.76-1.80.40051360.32042834X-RAY DIFFRACTION99.97
1.8-1.830.36461600.30372808X-RAY DIFFRACTION99.97
1.83-1.870.4091320.29342857X-RAY DIFFRACTION99.9
1.87-1.920.29241280.28092797X-RAY DIFFRACTION100
1.92-1.960.3231490.25452824X-RAY DIFFRACTION100
1.96-2.020.30321450.23172819X-RAY DIFFRACTION100
2.02-2.080.23421310.21622834X-RAY DIFFRACTION100
2.08-2.140.2551060.2112898X-RAY DIFFRACTION100
2.14-2.220.25791370.20682832X-RAY DIFFRACTION99.97
2.22-2.310.25271420.20472834X-RAY DIFFRACTION99.93
2.31-2.410.27321460.20542831X-RAY DIFFRACTION99.77
2.41-2.540.25751500.19972844X-RAY DIFFRACTION99.97
2.54-2.70.25381470.2022863X-RAY DIFFRACTION100
2.7-2.910.24891620.20432839X-RAY DIFFRACTION99.97
2.91-3.20.24571520.20032889X-RAY DIFFRACTION99.9
3.2-3.660.22291630.18562864X-RAY DIFFRACTION99.8
3.66-4.620.20131410.16012919X-RAY DIFFRACTION99.64
Refinement TLS params.Method: refined / Origin x: 12.4819168082 Å / Origin y: -2.19583359294 Å / Origin z: -12.795661097 Å
111213212223313233
T0.18301493855 Å2-0.0160190254474 Å20.00137062731398 Å2-0.215017925382 Å2-0.016409029962 Å2--0.205969613087 Å2
L0.126722532695 °2-0.274441955296 °2-0.321223429663 °2-0.742632939718 °20.531304998043 °2--0.63164647091 °2
S0.0200564150865 Å °0.0424016124781 Å °0.038819066282 Å °0.0590261531465 Å °-0.0693706567064 Å °-0.00430875928062 Å °0.0321143383633 Å °-0.0684262669151 Å °-0.00509429633755 Å °
Refinement TLS groupSelection details: all

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