Why structurally different cyclic peptides can be glycomimetics of the HNK-1 carbohydrate antigen.
The cyclic peptides c-(LSETTl) and c-(RTLPFS) are of potential clinical interest--they stimulate neurite outgrowth in a way that is similar to the effects of the HNK-1 (human natural killer cell-1) antigenic carbohydrate chains, which are terminated by 3'-sulfated glucuronic acid attached to an N-acetyllactosamine unit. To investigate the structure-activity relationships of the ability of the cyclic peptides to mimic HNK-1 carbohydrates, conformational analysis and examination of hydrophobic and hydrophilic patterns were performed and compared with the characteristics of a synthetic HNK-1 trisaccharide derivative. Data obtained demonstrate that both the trisaccharide and the glycomimetic peptide c-(LSETTl) exhibit a similar relationship between their hydrophobic moieties and their negatively charged sites. However, the second cyclic glycomimetic peptide investigated here, c-(RTLPFS), has a positively charged group as a potential contact point due to its Arg residue. Therefore, we studied the amino acid composition of all known receptor structures in the Protein Data Bank that are in contact with uronic acid and/or sulfated glycans. Interactions of the HNK-1 trisaccharide, c-(LSETTl), and c-(RTLPFS) with a laminin fragment involved in HNK-1 carbohydrate binding (i.e., the 21mer peptide: KGVSSRSYVGCIKNLEISRST) were also analyzed. Because the structure of the HNK-1-binding laminin domain is not available in the Protein Data Bank, we used the HNK-1-binding 21mer peptide fragment of laminin for the construction of a model receptor that enabled us to compare the molecular interplay of the HNK-1 trisaccharide and the two cyclopeptides c-(LSETTl) and c-(RTLPFS) with a reliable receptor structure in considerable detail.
Bhunia
Anirban
A
Institut für Biochemie und Endokrinologie, Veterinrmedizinische Fakultät, Justus-Liebig-Universität Giessen, Frankfurter Str. 100, 35392 Giessen, Germany.
Vivekanandan
Subramanian
S
Eckert
Thomas
T
Burg-Roderfeld
Monika
M
Wechselberger
Rainer
R
Romanuka
Julija
J
Bächle
Dirk
D
Kornilov
Andrei V
AV
von der Lieth
Claus-Wilhelm
CW
Jiménez-Barbero
Jesús
J
Nifantiev
Nikolay E
NE
Schachner
Melitta
M
Sewald
Norbert
N
Lütteke
Thomas
T
Hans-Joachim
Gabius
G
Siebert
Hans-Christian
HC
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002236:Carbohydrate Conformation; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000737:chemistry*; D019295:Computational Biology; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D006801:Humans; D007694:Killer Cells, Natural; D007797:Laminin / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014574:Uronic Acids / Q000737:chemistry; D014867:Water / Q000737:chemistry
D000941:Antigens; D002241:Carbohydrates; D007797:Laminin; D010456:Peptides, Cyclic; D014574:Uronic Acids; D014867:Water; D004121:Dimethyl Sulfoxide