PMID- 19760665
OWN - NLM
STAT- MEDLINE
DCOM- 20100212
LR  - 20211020
IS  - 1469-896X (Electronic)
IS  - 0961-8368 (Print)
IS  - 0961-8368 (Linking)
VI  - 18
IP  - 11
DP  - 2009 Nov
TI  - Crystal structures of a therapeutic single chain antibody in complex with two 
      drugs of abuse-Methamphetamine and 3,4-methylenedioxymethamphetamine.
PG  - 2336-45
LID - 10.1002/pro.244 [doi]
AB  - Methamphetamine (METH) is a major drug threat in the United States and worldwide. 
      Monoclonal antibody (mAb) therapy for treating METH abuse is showing exciting 
      promise and the understanding of how mAb structure relates to function will be 
      essential for future development of these important therapies. We have determined 
      crystal structures of a high affinity anti-(+)-METH therapeutic single chain 
      antibody fragment (scFv6H4, K(D)= 10 nM) derived from one of our candidate mAb in 
      complex with METH and the (+) stereoisomer of another abused drug, 
      3,4-methylenedioxymethamphetamine (MDMA), known by the street name "ecstasy." The 
      crystal structures revealed that scFv6H4 binds to METH and MDMA in a deep pocket 
      that almost completely encases the drugs mostly through aromatic interactions. In 
      addition, the cationic nitrogen of METH and MDMA forms a salt bridge with the 
      carboxylate group of a glutamic acid residue and a hydrogen bond with a histidine 
      side chain. Interestingly, there are two water molecules in the binding pocket 
      and one of them is positioned for a C--H...O interaction with the aromatic ring 
      of METH. These first crystal structures of a high affinity therapeutic antibody 
      fragment against METH and MDMA (resolution = 1.9 A, and 2.4 A, respectively) 
      provide a structural basis for designing the next generation of higher affinity 
      antibodies and also for carrying out rational humanization.
FAU - Celikel, Reha
AU  - Celikel R
AD  - Department of Physiology and Biophysics, College of Medicine, University of 
      Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
FAU - Peterson, Eric C
AU  - Peterson EC
FAU - Owens, S Michael
AU  - Owens SM
FAU - Varughese, Kottayil I
AU  - Varughese KI
LA  - eng
SI  - PDB/3GKZ
SI  - PDB/3GM0
GR  - DA018039/DA/NIDA NIH HHS/United States
GR  - R01 DA011560-08/DA/NIDA NIH HHS/United States
GR  - F32 DA018039/DA/NIDA NIH HHS/United States
GR  - R01 DA011560/DA/NIDA NIH HHS/United States
GR  - R01 DA011560-09/DA/NIDA NIH HHS/United States
GR  - HL55375/HL/NHLBI NIH HHS/United States
GR  - DA11560/DA/NIDA NIH HHS/United States
GR  - R01 DA026423/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Protein Sci
JT  - Protein science : a publication of the Protein Society
JID - 9211750
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Illicit Drugs)
RN  - 0 (Immunoglobulin Variable Region)
RN  - 059QF0KO0R (Water)
RN  - 44RAL3456C (Methamphetamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Antibodies, Monoclonal/*chemistry/genetics/metabolism
MH  - Binding Sites, Antibody
MH  - Hydrophobic and Hydrophilic Interactions
MH  - Illicit Drugs/*chemistry/metabolism
MH  - Immunoglobulin Variable Region/*chemistry/genetics/metabolism
MH  - Methamphetamine/*chemistry/metabolism
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*chemistry/metabolism
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Protein Binding
MH  - Water/metabolism
PMC - PMC2788288
EDAT- 2009/09/18 06:00
MHDA- 2010/02/13 06:00
PMCR- 2010/11/01
CRDT- 2009/09/18 06:00
PHST- 2009/09/18 06:00 [entrez]
PHST- 2009/09/18 06:00 [pubmed]
PHST- 2010/02/13 06:00 [medline]
PHST- 2010/11/01 00:00 [pmc-release]
AID - 10.1002/pro.244 [doi]
PST - ppublish
SO  - Protein Sci. 2009 Nov;18(11):2336-45. doi: 10.1002/pro.244.