TY - JOUR

T1 - High-resolution crystal structure of the Mu8.1 conotoxin from Conus mucronatus

AU - Müller, Emilie

AU - Hackney, Celeste Menuet

AU - Ellgaard, Lars

AU - Morth, Jens Preben

N1 - open access.

PY - 2023

Y1 - 2023

N2 - Marine cone snails produce a wealth of peptide toxins (conotoxins) that bind their molecular targets with high selectivity and potency. Therefore, conotoxins constitute valuable biomolecular tools with a variety of biomedical purposes. The Mu8.1 conotoxin from Conus mucronatus is the founding member of the newly identified saposin-like conotoxin class of conotoxins and has been shown to target Cav2.3, a voltage-gated calcium channel. Two crystal structures have recently been determined of Mu8.1 at 2.3 and 2.1 Å resolution. Here, a high-resolution crystal structure of Mu8.1 was determined at 1.67 Å resolution in the high-symmetry space group I4122. The asymmetric unit contained one molecule, with a symmetry-related molecule generating a dimer equivalent to that observed in the two previously determined structures. The high resolution allows a detailed atomic analysis of a water-filled cavity buried at the dimer interface, revealing a tightly coordinated network of waters that shield a lysine residue (Lys55) with a predicted unusually low side-chain pKa value. These findings are discussed in terms of a potential functional role of Lys55 in target interaction.

AB - Marine cone snails produce a wealth of peptide toxins (conotoxins) that bind their molecular targets with high selectivity and potency. Therefore, conotoxins constitute valuable biomolecular tools with a variety of biomedical purposes. The Mu8.1 conotoxin from Conus mucronatus is the founding member of the newly identified saposin-like conotoxin class of conotoxins and has been shown to target Cav2.3, a voltage-gated calcium channel. Two crystal structures have recently been determined of Mu8.1 at 2.3 and 2.1 Å resolution. Here, a high-resolution crystal structure of Mu8.1 was determined at 1.67 Å resolution in the high-symmetry space group I4122. The asymmetric unit contained one molecule, with a symmetry-related molecule generating a dimer equivalent to that observed in the two previously determined structures. The high resolution allows a detailed atomic analysis of a water-filled cavity buried at the dimer interface, revealing a tightly coordinated network of waters that shield a lysine residue (Lys55) with a predicted unusually low side-chain pKa value. These findings are discussed in terms of a potential functional role of Lys55 in target interaction.

U2 - 10.1107/S2053230X23007070

DO - 10.1107/S2053230X23007070

M3 - Journal article

C2 - 37642664

VL - 79

SP - 240

EP - 246

JO - Acta Crystallographica Section F: Structural Biology Communications

JF - Acta Crystallographica Section F: Structural Biology Communications

SN - 2053-230X

IS - 9

ER -