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TitleDesign and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 8064, Year 2023
Publish dateDec 6, 2023
AuthorsEdin Muratspahić / Kristine Deibler / Jianming Han / Nataša Tomašević / Kirtikumar B Jadhav / Aina-Leonor Olivé-Marti / Nadine Hochrainer / Roland Hellinger / Johannes Koehbach / Jonathan F Fay / Mohammad Homaidur Rahman / Lamees Hegazy / Timothy W Craven / Balazs R Varga / Gaurav Bhardwaj / Kevin Appourchaux / Susruta Majumdar / Markus Muttenthaler / Parisa Hosseinzadeh / David J Craik / Mariana Spetea / Tao Che / David Baker / Christian W Gruber /
PubMed AbstractDespite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single ...Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-β-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-β-NalA-KOR-Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions.
External linksNat Commun / PubMed:38052802 / PubMed Central
MethodsEM (single particle)
Resolution2.54 Å
Structure data

29026

8feg

EMDB-29026, PDB-8feg:
CryoEM structure of Kappa Opioid Receptor bound to a semi-peptide and Gi1
Method: EM (single particle) / Resolution: 2.54 Å

EMDB-42601: CryoEM structure of Kappa Opioid Receptor bound to a semi-peptide and Gi1
Method: EM (single particle) / Resolution: 2.54 Å

Chemicals

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / GPCR / KAPPA OPIOID Receptor / ROSETTA

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