Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

OPRM1 (P35372) - Overview - Molecular Target Synopsis

Protein


OPRM1, Mu-type opioid receptor
UniProt P35372

Also Known as OPRM_HUMAN, OPRM1, MOR1

Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:7905839, PubMed:7957926, PubMed:7891175, PubMed:12589820, PubMed:9689128). Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors (PubMed:7905839). The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling whereas morphine induces only low desensitization and endocytosis. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 12 couples to GNAS and is proposed to be involved in excitatory effects (PubMed:20525224). Isoform 16 and isoform 17 do not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity (PubMed:16580639). Forms homooligomers and heterooligomers with other GPCRs, such as OPRD1, OPRK1, OPRL1, NPFFR2, ADRA2A, SSTR2, CNR1 and CCR5 (probably in dimeric forms) (PubMed:12413885, PubMed:15778451, PubMed:15967873, PubMed:17224450). Interacts with heterotrimeric G proteins; interaction with a heterotrimeric complex containing GNAI1, GNB1 and GNG2 stabilizes the active conformation of the receptor and increases its affinity for endomorphin-2, the synthetic opioid peptide DAMGO and for morphinan agonists (By similarity). Interacts with PPL; the interaction disrupts agonist-mediated G-protein activation (PubMed:12810704). Interacts (via C-terminus) with DNAJB4 (via C-terminus) (PubMed:16542645). Interacts with calmodulin; the interaction inhibits the constitutive activity of OPRM1; it abolishes basal and attenuates agonist-stimulated G-protein coupling (PubMed:10419536, PubMed:10899953). Interacts with FLNA, PLD2, RANBP9 and WLS and GPM6A (PubMed:12519790, PubMed:14573758, PubMed:19788913, PubMed:20214800). Interacts with RTP4 (By similarity). Interacts with SYP and GNAS (By similarity). Interacts with RGS9, RGS17, RGS20, RGS4, PPP1R9B and HINT1.

Isoforms / Transcripts (Protein Coding)


Drugs


OPRM1 is targeted by Approved Drugs Eluxadoline, Oxymorphone Hydrochloride, Nalbuphine, Levorphanol, Alvimopan, Levomethadyl Acetate, Remifentanil, Codeine, Naltrexone, Meperidine, Fentanyl, Buprenorphine, Methadone, Oxycodone, Oxymorphone, Difenoxin, Sufentanil, Naloxone, Dihydrocodeine, Naldemedine, Pentazocine, Loperamide, Diphenoxylate, Hydrocodone. (see details)
Eluxadoline
Oxymorphone Hydrochloride
Nalbuphine
Levorphanol
Alvimopan
Levomethadyl Acetate
Remifentanil
Codeine
Naltrexone
Meperidine
Fentanyl
Buprenorphine
Methadone
Oxycodone
Oxymorphone
Difenoxin
Sufentanil
Naloxone
Dihydrocodeine
Naldemedine
Pentazocine
Loperamide
Diphenoxylate
Hydrocodone

Sub-cellular localization


UniProt: OPRM1 is active in the following subcellular-locations: axon, cell membrane, cell projection, cytoplasm, dendrite, endosome, perikaryon.
GO terms: OPRM1 is active in the following subcellular-locations: axon, cell, dendrite, dendrite cytoplasm, dendrite membrane, endoplasmic reticulum, endosome, focal adhesion, Golgi apparatus, integral component of plasma membrane, membrane raft, neuron projection, perikaryon, plasma membrane, postsynapse, sarcolemma.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project OPRM1 has gain in 0 cell-lines, loss in 3 cell-lines and no signal in 1002 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MCF7, HOP_92, CAKI_1

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: Hs 746T, NCI-H209, LN-18

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, NHLF, HSMM

(see details)

RNA Interference


OPRM1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: . (see details)

3D Structures


At greater than 90% identity similarity to OPRM1 there are:
4 structures (4 chains) solved
2 are solved in complex with at least one small molecule ligand
2 are solved with an approved drug

OPRM1 is solved in complex with the approved drug(s):

CLR/CHOLESTEROL (4DKL_A, 5C1M_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


OPRM1 has been screened with 6967 compounds (13298 bioactivities), 2898 compounds have bioactivities that show binding affinity of <= 500nM (4611 bioactivities). (see details)