PMID- 18052043
OWN - NLM
STAT- MEDLINE
DCOM- 20080227
LR  - 20071218
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 46
IP  - 51
DP  - 2007 Dec 25
TI  - Structural analysis of immunotherapeutic peptides for autoimmune Myasthenia 
      gravis.
PG  - 14987-95
AB  - Myasthenia gravis (MG) and its animal model, experimental MG (EAMG), are 
      autoimmune disorders in which major pathogenic antibodies are directed against 
      the main immunogenic region (MIR) of the nicotinic acetylcholine receptor 
      (nAChR). In an earlier attempt to develop peptide mimotopes capable of preventing 
      the anti-MIR-mediated pathogenicity, the peptide Pep.1 was initially identified 
      from phage display, and subsequently, Cyclic extended Pep.1 (Cyc.ext.Pep.1), 
      which incorporates eight additional residues into the Pep.1 sequence and has an 
      affinity for the anti-MIR antibody mAb198 3 orders of magnitude greater than that 
      of Pep.1, was developed. In an animal model, Pep.1 shows no ability to inhibit 
      mAb198-induced EAMG, whereas Cyc.ext.Pep.1 successfully blocks anti-MIR antibody 
      198 (mAb198)-induced EAMG. Our aim in this study was to identify the structural 
      characteristics related to the different affinities for mAb198 of Pep.1 and 
      Cyc.ext.Pep.1 using NMR spectroscopy and alanine scanning analysis. The NMR 
      structural analysis revealed that Pep.1 is very flexible in solution, whereas 
      Cyc.ext.Pep.1 is highly rigid within a region containing several turn structures. 
      Interestingly, TRNOE experiments revealed that mAb198-bound Pep.1, particularly 
      in the region between Asn7 and Glu11, shows significant structural similarity to 
      the region between Asn10 and Glu14 of Cyc.ext.Pep.1, which is critical for 
      interaction with mAb198. We therefore conclude the higher affinity of 
      Cyc.ext.Pep.1 for mAb198 reflects the fact that incorporation of additional 
      residues producing a single disulfide bond endows Pep.1 with a conformational 
      rigidity that mimics the structure of mAb198-bound Pep.1. Furthermore, our 
      results suggest that cyclic extended peptides could be utilized generally as 
      useful tools to optimize the affinity of phage library-derived peptide antigens.
FAU - Jung, Hyun Ho
AU  - Jung HH
AD  - Department of Life Sciences, Research Center for Biomolecular Nanotechnology, 
      Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
FAU - Yi, Hwa Jung
AU  - Yi HJ
FAU - Lee, Seung Kyu
AU  - Lee SK
FAU - Lee, Ju Yeon
AU  - Lee JY
FAU - Jung, Hoi Jong
AU  - Jung HJ
FAU - Yang, Sung Tae
AU  - Yang ST
FAU - Eu, Young-Jae
AU  - Eu YJ
FAU - Im, Sin-Hyeog
AU  - Im SH
FAU - Kim, Jae Il
AU  - Kim JI
LA  - eng
SI  - PDB/2JRV
SI  - PDB/2JRW
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071201
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Peptide Fragments)
RN  - 0 (Receptors, Nicotinic)
SB  - IM
MH  - Antibodies, Monoclonal/immunology
MH  - Humans
MH  - Models, Molecular
MH  - Myasthenia Gravis/*immunology
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Peptide Fragments/chemical synthesis/*chemistry/*immunology
MH  - Protein Structure, Tertiary
MH  - Receptors, Nicotinic/*chemistry/*immunology
EDAT- 2007/12/07 09:00
MHDA- 2008/02/28 09:00
CRDT- 2007/12/07 09:00
PHST- 2007/12/07 09:00 [pubmed]
PHST- 2008/02/28 09:00 [medline]
PHST- 2007/12/07 09:00 [entrez]
AID - 10.1021/bi701298b [doi]
PST - ppublish
SO  - Biochemistry. 2007 Dec 25;46(51):14987-95. doi: 10.1021/bi701298b. Epub 2007 Dec 
      1.