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Fig. 1. The best ligand pose of YPELPK (black)with hnRNP M. The van der Waals surface ofhnRNP M is in gray.side-chain in A1, than when the sidechainof Leus and Pro are replaced inA4 and A5, respectively, wasunexpected. The Tyr residueparticipates in a hydrogen bond andtwo weakly-polar interactions,whereas the Leu and Pro residues inpositions 4 and 5 do not have anydirect interactions with the receptor.Even replacing the charged sidechains,as in peptides A2 and A6 hasless loss of binding energy, 0.39 kcalmol -1 and 0.98 kcal mol -1 ,respectively, than replacing the Leuand Pro residues. Thus, theconformational rigidity given by theLeu and Pro residues seems to bemore important to binding than that byother side-chains, although, these mayalso participate in electrostatic orweakly polar interactions. YPELPK atμM concentrations, significantlyincreases IL-6 production by differentiated THP-1 cells (Figure 2). The Ala-scan analogs ofYPELPK activate THP-1 cells less than the parent peptide. A1 and A6, however, are stillable to stimulate IL-6 production (Figure 2). In summary, YPELPK, A1 and A6 arebiologically active at concentrations low enough that they can be used as core compoundsto develop an antagonist of CEA at the hnRNP M receptor.Fig. 2. IL-6 production of THP-1 cells treated with YPELPK and analogs. A, YPELPK;B, YPELPK and Ala-scan analogs. Significance of p < 0.05 is marked with a *.AcknowledgmentsThis work was supported by the NIH-INBRE grant P20 RR016469.References1. Bajenova, O.V., Zimmer, R., Stolper, E., Salisbury-Rowswell, J., Nanji, A., Thomas, P. J. Biol.Chem. 276, 31067-31073 (2001).2. Gangopadhyay, A., Bajenova, O., Kelly, T. M., Thomas, P. Cancer Res. 56, 4805-4810 (1996).3. Sugita, Y., Okamoto, Y. Chem. Phys. Lett. 314, 141-151 (1999).4. Kaminski, G.A., Friesner, R.A., Tirado-Rives, J., Jorgensen, W.L. J. Phys. Chem. B. 105, 6474-6487(2001).5. van der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E., Berendsen, H.J.C. J. Comput.Chem. 26, 1701-1718 (2005).507