P05484 (CO17A_CONMA) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names	Recommended name: Omega-conotoxin MVIIA Alternative name(s): SNX-111 INN=Ziconotide
Organism	Conus magus (Magus cone) (Magician's cone snail)
Taxonomic identifier	6492 [NCBI]
Taxonomic lineage	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Protostomia › Lophotrochozoa › Mollusca › Gastropoda › Caenogastropoda › Hypsogastropoda › Neogastropoda › Conoidea › Conidae › Conus

Protein attributes

Sequence length	71 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Omega-conotoxins act at presynaptic membranes, they bind and block voltage-gated calcium channels. This toxin blocks N-type calcium channels (Cav2.2/CACNA1B).
Subcellular location	Secreted.
Tissue specificity	Expressed by the venom duct.
Domain	The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin. The cysteine framework is VI/VII (C-C-CC-C-C).
Pharmaceutical use	Is available under the names Prialt by Neurex. It blocks acute pain in patients who no longer obtain relief from opiate drugs. It is 100 to 1000 times more potent than morphine. By blocking calcium channels it disable nerves that transmit pain signals.
Sequence similarities	Belongs to the conotoxin O1 superfamily.

Ontologies

Keywords
Cellular component	Secreted
Domain	Knottin Signal
Molecular function	Calcium channel inhibitor Ion channel impairing toxin Neurotoxin Presynaptic neurotoxin Toxin
PTM	Amidation Disulfide bond
Technical term	3D-structure Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Biological_process	pathogenesis Inferred from electronic annotation. Source: InterPro
Cellular_component	other organism presynaptic membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	calcium channel inhibitor activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Potential

Propeptide

23 – 45

23

PRO_0000034914

Peptide

46 – 70

25

Omega-conotoxin MVIIA Ref.3 Ref.4

PRO_0000034915

Sites

Site

58

1

Important for calcium channel binding

Amino acid modifications

Modified residue

70

1

Cysteine amide

Disulfide bond

46 ↔ 61

Ref.5 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13

Disulfide bond

53 ↔ 65

Ref.5 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13

Disulfide bond

60 ↔ 70

Ref.5 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13

Experimental info

Mutagenesis

47

1

K → A: Little decrease in activity. Ref.6

Mutagenesis

58

1

Y → A: Strong decrease in activity. Ref.6

Sequence conflict

42

1

T → M in ADB93081. Ref.2

Secondary structure

1

.

.

.

.

.

.

71

Helix Strand Turn

Details...

Beta strand

55 – 57

3

Beta strand

60 – 63

4

Beta strand

69 – 71

3

Sequences

	Sequence		Length	Mass (Da)
	P05484 [UniParc]. Last modified June 20, 2002. Version 2. Checksum: E2A32725C81AF31D	FASTA	71	7,587
	10 20 30 40 50 60 MKLTCVVIVA VLLLTACQLI TADDSRGTQK HRALRSTTKL STSTRCKGKG AKCSRLMYDC 70 CTGSCRSGKC G

References

[1]	"Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes." Lewis R.J., Nielsen K.J., Craik D.J., Loughnan M.L., Adams D.A., Sharpe I.A., Luchian T., Adams D.J., Bond T., Thomas L., Jones A., Matheson J.-L., Drinkwater R., Andrews P.R., Alewood P.F. J. Biol. Chem. 275:35335-35344(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Venom duct.
[2]	"Evolution of Conus peptide toxins: analysis of Conus californicus Reeve, 1844." Biggs J.S., Watkins M., Puillandre N., Ownby J.P., Lopez-Vera E., Christensen S., Moreno K.J., Bernaldez J., Licea-Navarro A., Corneli P.S., Olivera B.M. Mol. Phylogenet. Evol. 56:1-12(2010) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Peptide neurotoxins from fish-hunting cone snails." Olivera B.M., Gray W.R., Zeikus R.D., McIntosh J.M., Varga J., Rivier J.E., de Santos V., Cruz L.J. Science 230:1338-1343(1985) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 46-70.
[4]	"Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom." Olivera B.M., Cruz L.J., de Santos V., Lecheminant G.W., Griffin D., Zeikus R.D., McIntosh J.M., Galyean R., Varga J., Gray W.R., Rivier J.E. Biochemistry 26:2086-2090(1987) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 46-70.
[5]	"Determination of disulfide bridge pattern in omega-conopeptides." Chung D., Gaur S., Bell J.R., Ramachandran J., Nadasdi L. Int. J. Pept. Protein Res. 46:320-325(1995) [PubMed] [Europe PMC] [Abstract] Cited for: DISULFIDE BONDS.
[6]	"Tyr13 is essential for the activity of omega-conotoxin MVIIA and GVIA, specific N-type calcium channel blockers." Kim J.-I., Takahashi M., Ohtake A., Wakamiya A., Sato K. Biochem. Biophys. Res. Commun. 206:449-454(1995) [PubMed] [Europe PMC] [Abstract] Cited for: SYNTHESIS OF 46-70, MUTAGENESIS OF LYS-47 AND TYR-58.
[7]	"Ziconotide: neuronal calcium channel blocker for treating severe chronic pain." Miljanich G.P. Curr. Med. Chem. 11:3029-3040(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHARMACEUTICAL USE FOR SEVERE CHRONIC PAIN TREATMENT.
[8]	"Three-dimensional structure in solution of the calcium channel blocker omega-conotoxin MVIIA." Kohno T., Kim J.-I., Kobayashi K., Kodera Y., Maeda T., Sato K. Biochemistry 34:10256-10265(1995) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 46-70, DISULFIDE BONDS.
[9]	"Solution structure of omega-conotoxin MVIIA using 2D NMR spectroscopy." Basus V.J., Nadasdi L., Ramachandran J., Miljanich G.P. FEBS Lett. 370:163-169(1995) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 46-70, DISULFIDE BONDS.
[10]	"A consensus structure for omega-conotoxins with different selectivities for voltage-sensitive calcium channel subtypes: comparison of MVIIA, SVIB and SNX-202." Nielsen K.J., Thomas L., Lewis R.J., Alewood P.F., Craik D.J. J. Mol. Biol. 263:297-310(1996) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 46-70, DISULFIDE BONDS.
[11]	"Structure-activity relationships of omega-conotoxins MVIIA, MVIIC and 14 loop splice hybrids at N and P/Q-type calcium channels." Nielsen K.J., Adams D., Thomas L., Bond T., Alewood P.F., Craik D.J., Lewis R.J. J. Mol. Biol. 289:1405-1421(1999) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 46-70, DISULFIDE BONDS.
[12]	"Structural and dynamic characterization of omega-conotoxin MVIIA: the binding loop exhibits slow conformational exchange." Atkinson R.A., Kieffer B., Dejaegere A., Sirockin F., Lefevre J.-F. Biochemistry 39:3908-3919(2000) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 46-70, DISULFIDE BONDS.
[13]	"Solution structure and backbone dynamics of an omega-conotoxin precursor." Goldenberg D.P., Koehn R.E., Gilbert D.E., Wagner G. Protein Sci. 10:538-550(2001) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 46-70, DISULFIDE BONDS.
+	Additional computationally mapped references.

Web resources

Ziconotide Source

Web site on ziconotide

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

FJ959111 Genomic DNA. Translation: ADB93081.1.

PIR

JH0700.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DW4	NMR	-	A	46-70	[»]
1DW5	NMR	-	A	46-70	[»]
1FEO	NMR	-	A	46-71	[»]
1MVI	NMR	-	A	46-70	[»]
1OMG	NMR	-	A	46-70	[»]
1TT3	NMR	-	A	46-70	[»]
1TTK	NMR	-	A	46-70	[»]

ModBase

Search...

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Organism-specific databases

ConoServer

1564. MVIIA precursor.

Family and domain databases

InterPro

IPR004214. Conotoxin.
IPR012321. Conotoxin_omega-typ_CS.
[Graphical view]

Pfam

PF02950. Conotoxin. 1 hit.
[Graphical view]

PROSITE

PS60004. OMEGA_CONOTOXIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P05484.

Entry information

Entry name

CO17A_CONMA

Accession

Primary (citable) accession number: P05484
Secondary accession number(s): D6C4G9

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1988
Last sequence update:	June 20, 2002
Last modified:	April 3, 2013
This is version 96 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Animal Toxin Annotation Program