4LAS

Crystal structure of a therapeutic single chain antibody in complex with 4-hydroxymethamphetamine

Summary for 4LAS

• Entry DOI: 10.2210/pdb4las/pdb
• Related: 3GKZ 4LAQ 4LAR
• Descriptor: Single chain antibody fragment scFv6H4, 4-[(2S)-2-(methylamino)propyl]phenol (3 entities in total)
• Functional Keywords: methamphetamine, anti-methamphetamine antibody, therapeutic antibody, scfv, immune system
• Biological source: Mus musculus (mouse)
• Total number of polymer chains: 1
• Total formula weight: 26957.58

Authors

Celical, R.,Gokulan, K.,Peterson, E.C.,Varughese, K.I. (deposition date: 2013-06-20, release date: 2013-12-11, Last modification date: 2024-10-30)

Primary citation

Peterson, E.C.,Celikel, R.,Gokulan, K.,Varughese, K.I.
Structural characterization of a therapeutic anti-methamphetamine antibody fragment: oligomerization and binding of active metabolites.
Plos One, 8:e82690-e82690, 2013

PubMed Abstract: Vaccines and monoclonal antibodies (mAb) for treatment of (+)-methamphetamine (METH) abuse are in late stage preclinical and early clinical trial phases, respectively. These immunotherapies work as pharmacokinetic antagonists, sequestering METH and its metabolites away from sites of action in the brain and reduce the rewarding and toxic effects of the drug. A key aspect of these immunotherapy strategies is the understanding of the subtle molecular interactions important for generating antibodies with high affinity and specificity for METH. We previously determined crystal structures of a high affinity anti-METH therapeutic single chain antibody fragment (scFv6H4, K(D) = 10 nM) in complex with METH and the (+) stereoisomer of 3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy"). Here we report the crystal structure of scFv6H4 in homo-trimeric unbound (apo) form (2.60Å), as well as monomeric forms in complex with two active metabolites; (+)-amphetamine (AMP, 2.38Å) and (+)-4-hydroxy methamphetamine (p-OH-METH, 2.33Å). The apo structure forms a trimer in the crystal lattice and it results in the formation of an intermolecular composite beta-sheet with a three-fold symmetry. We were also able to structurally characterize the coordination of the His-tags with Ni(2+). Two of the histidine residues of each C-terminal His-tag interact with Ni(2+) in an octahedral geometry. In the apo state the CDR loops of scFv6H4 form an open conformation of the binding pocket. Upon ligand binding, the CDR loops adopt a closed formation, encasing the drug almost completely. The structural information reported here elucidates key molecular interactions important in anti-methamphetamine abuse immunotherapy.

PubMed: 24349338
DOI: 10.1371/journal.pone.0082690

Experimental method

X-RAY DIFFRACTION (2.33 Å)