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Basic information

Entry
Database: PDB / ID: 9pln
TitleLocally-refined structure of alpha2a adrenergic receptor in complex with Go heterotrimer, scFv16, and N-(5-methylnaphthalen-1-yl)pyridin-4-amine (compound 4905)
ComponentsAlpha-2A adrenergic receptor
KeywordsMEMBRANE PROTEIN / Receptor / Drug / Complex / GPCR / G-protein / scFv16
Function / homology
Function and homology information


negative regulation of uterine smooth muscle contraction / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / alpha-2C adrenergic receptor binding / epinephrine binding / phospholipase C-activating adrenergic receptor signaling pathway / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of epinephrine secretion ...negative regulation of uterine smooth muscle contraction / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / alpha-2C adrenergic receptor binding / epinephrine binding / phospholipase C-activating adrenergic receptor signaling pathway / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of epinephrine secretion / negative regulation of calcium ion-dependent exocytosis / response to alcohol / heterotrimeric G-protein binding / intestinal absorption / positive regulation of potassium ion transport / thioesterase binding / dopaminergic synapse / thermoception / Surfactant metabolism / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / norepinephrine binding / positive regulation of membrane protein ectodomain proteolysis / Adrenoceptors / adrenergic receptor signaling pathway / positive regulation of wound healing / response to morphine / negative regulation of calcium ion transport / positive regulation of epidermal growth factor receptor signaling pathway / Rho protein signal transduction / negative regulation of insulin secretion / negative regulation of lipid catabolic process / regulation of vasoconstriction / cellular response to hormone stimulus / adenylate cyclase-activating adrenergic receptor signaling pathway / presynaptic active zone membrane / presynaptic modulation of chemical synaptic transmission / axon terminus / positive regulation of cytokine production / female pregnancy / platelet activation / vasodilation / GABA-ergic synapse / postsynaptic density membrane / epidermal growth factor receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / actin cytoskeleton organization / glucose homeostasis / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / DNA replication / G alpha (i) signalling events / basolateral plasma membrane / Ras protein signal transduction / positive regulation of MAPK cascade / signaling receptor complex / positive regulation of cell migration / G protein-coupled receptor signaling pathway / neuronal cell body / positive regulation of cell population proliferation / protein kinase binding / glutamatergic synapse / protein homodimerization activity / plasma membrane / cytoplasm
Similarity search - Function
Alpha 2A adrenoceptor / Adrenoceptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
: / Alpha-2A adrenergic receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsSrinivasan, K. / Xu, X. / Mailhot, O. / Manglik, A. / Shoichet, B.
Funding support United States, 1items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA) United States
Citation
Journal: Nature / Year: 2026
Title: Development of a random background to understand ligand optimization.
Authors: Xinyu Xu / Olivier Mailhot / Galen J Correy / Xi-Ping Huang / Joao M Braz / Da Shi / Karthik Srinivasan / Kara Zielinski / Yuliia Holota / Yuliia Kuziv / Christos Iliopoulos-Tsoutsouvas / ...Authors: Xinyu Xu / Olivier Mailhot / Galen J Correy / Xi-Ping Huang / Joao M Braz / Da Shi / Karthik Srinivasan / Kara Zielinski / Yuliia Holota / Yuliia Kuziv / Christos Iliopoulos-Tsoutsouvas / Nathan D Levinzon / Yagmur U Doruk / Moira M Rachman / Morgan E Diolaiti / Maisie G V Stevens / Fangyu Liu / Katie L Holland / Harald Hübner / Jing Wang / Yujin Wu / Alan Ashworth / Alexandros Makriyannis / Yuqi Zhang / Yurii S Moroz / Peter Gmeiner / Robert Abel / Aashish Manglik / Allan I Basbaum / Bryan L Roth / James S Fraser / Brian K Shoichet /
Abstract: Ligand optimization is central to drug discovery, with hundreds of analogues often designed and synthesized between an initial hit and a therapeutic candidate. The efficiency of this process is ...Ligand optimization is central to drug discovery, with hundreds of analogues often designed and synthesized between an initial hit and a therapeutic candidate. The efficiency of this process is unclear, partly because there is no random background for optimization to compare against. Such a random background might emerge from systematic random small substitutions across starting ligands, measuring the likelihood of achieving a substantial improvement in affinity or potency, or other property by any single perturbation. Recent literature has suggested that perhaps 10% of analogues with minor modifications improve upon the potency of a parent by tenfold or more, but this number is clouded by reporting bias, intentional improvement and inter-group variability. To begin to establish a background expectation for ligand optimization, here we systematically modified 18 lead molecules across six targets with single-atom changes; 257 compounds were synthesized. Unexpectedly, 11.3% of these random small perturbation analogues improved potency by tenfold or more. Conversely, they typically had worse in vitro pharmacokinetics. Although it was possible to find analogues where the potency increase compensated for inferior exposure and half-life, resulting in more potent compounds in vivo, overall, a frustrated landscape for ligand optimization is revealed. This study begins to establish a background expectation for ligand potency optimization and offers a simple strategy to do so. It also begins to quantify the challenges confronting the field in moving beyond in vitro potency.
#1: Journal: bioRxiv / Year: 2026
Title: Toward a Random Background for Ligand Optimization.
Abstract: Ligand optimization is central to drug discovery as hundreds of analogs might be designed and synthesized between an initial hit and a therapeutic candidate. The efficiency of this process is ...Ligand optimization is central to drug discovery as hundreds of analogs might be designed and synthesized between an initial hit and a therapeutic candidate. The efficiency of this process is unclear, at least partly because there is no random background for optimization against which to compare. Such a random background might emerge from synthetically accessible but otherwise systematic random small substitutions across starting ligands, measuring likelihood of achieving a substantial improvement in affinity/potency or other property by any single perturbation. Recent literature and ligand-affinity/potency databases suggest that perhaps 10% of analogs with minor modifications improve upon a parent's potency substantially (by ≥10-fold), but this number is clouded by reporting bias, intentional improvement, and inter-group reproducibility. To begin to establish a background expectation for ligand optimization, we comprehensively and systematically modified 18 lead molecules across six targets with single atom changes; 257 compounds were synthesized. Unexpectedly, 11.2% of these random small perturbation analogs improved potency by ≥10-fold over their parents. Conversely, these more potent analogs typically had worse pharmacokinetics (e.g. reduced metabolic stability, lower plasma free fraction). While it was possible to find analogs where the potency increase compensated for inferior exposure and half-life, resulting in more potent compounds in vivo, overall a frustrated landscape for ligand optimization is revealed. This study begins to establish a background expectation for ligand potency optimization and offers a simple strategy to do so. It also begins to quantify the challenges confronting the field in moving beyond in vitro potency.
History
DepositionJul 15, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release
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Description: Atomic clashes
Details: Reduced clashscore by modeling and refining with hydrogens. Removed a hydrogen from the pyridine nitrogen in ligand A1CIU, making it consistent with the existing CCD file.
Provider: author / Type: Coordinate replacement
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: Alpha-2A adrenergic receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,8782
Polymers53,6441
Non-polymers2341
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Alpha-2A adrenergic receptor / Alpha-2 adrenergic receptor subtype C10 / Alpha-2A adrenoreceptor / Alpha-2A adrenoceptor / Alpha-2AAR


Mass: 53643.855 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADRA2A, ADRA2R, ADRAR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08913
#2: Chemical ChemComp-A1CIU / N-(5-methylnaphthalen-1-yl)pyridin-4-amine


Mass: 234.296 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H14N2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Alpha2a adrenergic receptor in complex with Go heterotrimer, scFv16, and compound 4905.
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Details: CHS was solubilized in LMNG and GDN prior to diluting into buffers.
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2100 mMSodium chlorideNaCl1
30.0075 % w/vLauryl Maltose Neopentyl GlycolC47H88O221
40.0025 % w/vGlyco-diosgeninC56H92O251
50.001 % w/vCholesteryl hemisuccinateC31H50O41
60.01 mMN-(5-methylnaphthalen-1-yl)pyridin-4-amineC16H14N21
SpecimenConc.: 2.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 15 mA current / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 0.596 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 10305

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX2.0_5936model refinement
5cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6609807
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 323827 / Symmetry type: POINT
Atomic model buildingB value: 110.6 / Protocol: RIGID BODY FIT
Atomic model buildingPDB-ID: 7EJ8

7ej8


Accession code: 7EJ8 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.8 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0042178
ELECTRON MICROSCOPYf_angle_d0.8112976
ELECTRON MICROSCOPYf_dihedral_angle_d6.315292
ELECTRON MICROSCOPYf_chiral_restr0.044354
ELECTRON MICROSCOPYf_plane_restr0.005354

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