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- PDB-8wkz: Crystal structure of the Melanocortin-4 Receptor (MC4R) in comple... -

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Basic information

Entry
Database: PDB / ID: 8wkz
TitleCrystal structure of the Melanocortin-4 Receptor (MC4R) in complex with S31
Components
  • Melanocortin receptor 4
  • [N-(3-{bis[2-(pyridin-2-yl-kappaN)ethyl]amino-kappaN}propyl)-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide](azido)(hydroxy)copper
KeywordsMEMBRANE PROTEIN / Ca++ cofactor / GPCR / PGS fusion / LCP
Function / homology
Function and homology information


regulation of eating behavior / melanocyte-stimulating hormone receptor activity / response to melanocyte-stimulating hormone / melanocortin receptor activity / regulation of grooming behavior / energy reserve metabolic process / neuropeptide binding / regulation of metabolic process / feeding behavior / insulin secretion ...regulation of eating behavior / melanocyte-stimulating hormone receptor activity / response to melanocyte-stimulating hormone / melanocortin receptor activity / regulation of grooming behavior / energy reserve metabolic process / neuropeptide binding / regulation of metabolic process / feeding behavior / insulin secretion / negative regulation of feeding behavior / diet induced thermogenesis / Transcriptional and post-translational regulation of MITF-M expression and activity / peptide hormone binding / positive regulation of bone resorption / Peptide ligand-binding receptors / response to insulin / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G alpha (s) signalling events / ubiquitin protein ligase binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Melanocortin 4 receptor / Melanocortin receptor 3-5 / Melanocortin/ACTH receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
OLEIC ACID / Melanocortin receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsGimenez, L.E. / Martin, C. / Yu, J. / Hollanders, C. / Hernandez, C. / Dahir, N.S. / Wu, Y. / Yao, D. / Han, G.W. / Wu, L. ...Gimenez, L.E. / Martin, C. / Yu, J. / Hollanders, C. / Hernandez, C. / Dahir, N.S. / Wu, Y. / Yao, D. / Han, G.W. / Wu, L. / Poorten, O.V. / Lamouroux, A. / Mannes, M. / Tourwe, D. / Zhao, S. / Stevens, R.C. / Cone, R.D. / Ballet, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design.
Authors: Gimenez, L.E. / Martin, C. / Yu, J. / Hollanders, C. / Hernandez, C.C. / Wu, Y. / Yao, D. / Han, G.W. / Dahir, N.S. / Wu, L. / Van der Poorten, O. / Lamouroux, A. / Mannes, M. / Zhao, S. / ...Authors: Gimenez, L.E. / Martin, C. / Yu, J. / Hollanders, C. / Hernandez, C.C. / Wu, Y. / Yao, D. / Han, G.W. / Dahir, N.S. / Wu, L. / Van der Poorten, O. / Lamouroux, A. / Mannes, M. / Zhao, S. / Tourwe, D. / Stevens, R.C. / Cone, R.D. / Ballet, S.
History
DepositionSep 28, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 7, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Melanocortin receptor 4
B: [N-(3-{bis[2-(pyridin-2-yl-kappaN)ethyl]amino-kappaN}propyl)-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide](azido)(hydroxy)copper
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,8448
Polymers61,3922
Non-polymers1,4526
Water362
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)167.460, 44.940, 89.570
Angle α, β, γ (deg.)90.00, 97.60, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Melanocortin receptor 4 / MC4-R


Mass: 60197.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MC4R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P32245
#2: Protein/peptide [N-(3-{bis[2-(pyridin-2-yl-kappaN)ethyl]amino-kappaN}propyl)-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide](azido)(hydroxy)copper


Mass: 1194.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C18H34O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
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: 2.74 Å3/Da / Density % sol: 55.05 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / Details: PEG 400, Bis-tris propane buffer, CaCl2-2H2O

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 10, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.3→44.46 Å / Num. obs: 10306 / % possible obs: 100 % / Redundancy: 16.46 % / CC1/2: 0.982 / Rmerge(I) obs: 0.583 / Net I/σ(I): 7.5
Reflection shellResolution: 3.3→3.42 Å / Rmerge(I) obs: 3.305 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 1029 / CC1/2: 0.553 / Rpim(I) all: 0.825 / Rrim(I) all: 3.409

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.3→44.39 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2718 480 4.68 %RANDOM
Rwork0.2132 ---
obs0.2159 10262 99.9 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.3→44.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3696 0 71 2 3769
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023835
X-RAY DIFFRACTIONf_angle_d0.4125168
X-RAY DIFFRACTIONf_dihedral_angle_d9.03561
X-RAY DIFFRACTIONf_chiral_restr0.038605
X-RAY DIFFRACTIONf_plane_restr0.004637
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.3-3.780.33421650.26873221X-RAY DIFFRACTION100
3.78-4.760.28881640.20213216X-RAY DIFFRACTION100
4.76-44.390.22021510.19493345X-RAY DIFFRACTION100

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