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Volumn 121, Issue 7, 1999, Pages 1434-1443

Remote binding energy in antibody catalysis: Studies of a catalytically unoptimized specificity pocket

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBODY; HAPTEN;

EID: 0033599302     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja983017e     Document Type: Article
Times cited : (8)

References (81)
  • 13
    • 0029925034 scopus 로고    scopus 로고
    • For an example of the design and functional characterization of an antibody binding site that was designed to exhibit broad specificity at the α-substituent of the amino acid substrate see: Tanaka, F., Kinoshita, K., Tanimura, R., Fujii, I. J. Am. Chem. Soc. 1996, 118, 2332-2339. The relaxation of substrate specificity at this position was accomplished by substituting the α-substituent with the linker.
    • (1996) J. Am. Chem. Soc. , vol.118 , pp. 2332-2339
    • Tanaka, F.1    Kinoshita, K.2    Tanimura, R.3    Fujii, I.4
  • 18
    • 0003518480 scopus 로고
    • John Wiley and Sons: New York
    • Segel, I. H. Enzyme Kinetics; John Wiley and Sons: New York, 1975; p 957.
    • (1975) Enzyme Kinetics , pp. 957
    • Segel, I.H.1
  • 19
    • 0345318758 scopus 로고    scopus 로고
    • The substrate corresponding to 1p is 1. The hydrolysis of phenyl acetate, the substrate that corresponds to the phosphonate, 11p, was not catalyzed by 17E8 (data not shown)
    • The substrate corresponding to 1p is 1. The hydrolysis of phenyl acetate, the substrate that corresponds to the phosphonate, 11p, was not catalyzed by 17E8 (data not shown).
  • 22
    • 0345318757 scopus 로고    scopus 로고
    • The substrate 13 was prepared as a 1:1 mixture of the cis and trans isomers whereas 12 was purely trans
    • The substrate 13 was prepared as a 1:1 mixture of the cis and trans isomers whereas 12 was purely trans.
  • 42
    • 0345318745 scopus 로고    scopus 로고
    • 3), respectively (see refs 40 and 41)
    • 3), respectively (see refs 40 and 41).
  • 46
    • 0344455778 scopus 로고    scopus 로고
    • However, the energetic cost needed for the antibody to constrain the side chain is not realized with the fixed rotamer mimick (13). This conformer is about 3.5 kcal/mol higher in energy than the staggered, low-energy conformer (see refs 40 and 41). Thus, structurally constraining the side chain should allow for this energy to be expressed in greater transition state stabilization. The decrease in activity (Tables 1 and 3) for 13 compared to 5 is most likely a result of the fact that the eis isomer does not resemble the bound rotamer precisely due to changes in the hybridization at the δ and γ carbons as well as differences in the dihedral angle between 13 and the actual bound rotamer. The alkene side chain is also less hydrophobic (than 5), thus raising the desolvation cost for binding. The fact that 14 was also a substrate suggests that the rotameric requirement is only important for the torsion angle defined by carbons Cb-Ce
    • However, the energetic cost needed for the antibody to constrain the side chain is not realized with the fixed rotamer mimick (13). This conformer is about 3.5 kcal/mol higher in energy than the staggered, low-energy conformer (see refs 40 and 41). Thus, structurally constraining the side chain should allow for this energy to be expressed in greater transition state stabilization. The decrease in activity (Tables 1 and 3) for 13 compared to 5 is most likely a result of the fact that the eis isomer does not resemble the bound rotamer precisely due to changes in the hybridization at the δ and γ carbons as well as differences in the dihedral angle between 13 and the actual bound rotamer. The alkene side chain is also less hydrophobic (than 5), thus raising the desolvation cost for binding. The fact that 14 was also a substrate suggests that the rotameric requirement is only important for the torsion angle defined by carbons Cb-Ce.
  • 47
    • 0344887575 scopus 로고    scopus 로고
    • The substrates 6 and 11 (and phosphonates 6p and 11p) were not included in the correlations because we believe that these molecules could not be accommodated without changes in pocket structure or binding mode, making the analysis of these compounds ambiguous
    • The substrates 6 and 11 (and phosphonates 6p and 11p) were not included in the correlations because we believe that these molecules could not be accommodated without changes in pocket structure or binding mode, making the analysis of these compounds ambiguous.
  • 49
    • 0026566303 scopus 로고
    • Although hydrophobicity may play a major role, there are other factors that are also expected to be major contributors to substrate and transition state binding including statistical entropic factors and enthalpic contributors from the formation of van der Waals packing interactions. Sneddon, F. S.; Tobias, D. J. Biochemistry 1992, 31, 2842-2846 and Morton, A.; Baase, W. A.; Mathews, B. W. Biochemistry 1995, 34, 8564- 8575.
    • (1992) Biochemistry , vol.31 , pp. 2842-2846
    • Sneddon, F.S.1    Tobias, D.J.2
  • 50
    • 0029016268 scopus 로고
    • Although hydrophobicity may play a major role, there are other factors that are also expected to be major contributors to substrate and transition state binding including statistical entropic factors and enthalpic contributors from the formation of van der Waals packing interactions. Sneddon, F. S.; Tobias, D. J. Biochemistry 1992, 31, 2842-2846 and Morton, A.; Baase, W. A.; Mathews, B. W. Biochemistry 1995, 34, 8564-8575.
    • (1995) Biochemistry , vol.34 , pp. 8564-8575
    • Morton, A.1    Baase, W.A.2    Mathews, B.W.3
  • 52
    • 0039384496 scopus 로고
    • Johnson, M. L., Ackers, G. K., Eds.; Academic Press: San Diego
    • Pace, C. N. In Methods in Enzymology; 1st ed.; Johnson, M. L., Ackers, G. K., Eds.; Academic Press: San Diego, 1995; Vol. 259; p 761.
    • (1995) Methods in Enzymology; 1st Ed. , vol.259 , pp. 761
    • Pace, C.N.1


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.