Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex (520 views)
Protein Sci (ISSN: 0961-8368, 1469-896xelectronic), 1998 Feb; 7(2): 243-253.
Export to BibTeX Export to EndNote
Paper type: Journal Article,
Impact factor: 4.44, 5-year impact factor: 3.602
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-0031890648&partnerID=40&md5=d81bc6e4a30626b70c66302ad4e6e62f
Keywords: Antithrombotics, Hirudin-Like Binding Mode, Hirunorms, Thrombin Synthetic Inhibitors, X-Ray Crystal Structure, Thrombin Inhibitor, Unclassified Drug, Article, Blood Clotting, Carboxy Terminal Sequence, Complex Formation, Crystallography, Human, Human Cell, Molecular Biology, Priority Journal, Protein Binding, Protein Interaction, Protein Structure, Antithrombins, Molecular Mimicry, Oligopeptides, Protein Conformation, Solvents,
Affiliations:
Ctro. Interuniversitario Ric. su P., Ctro. Stud. Biocristallografia - CNR, University of Napoli Federico II, via Mezzocannone 4, 80134 Napoli, Italy
Dipto. Biochim. Biotecnologie M., University of Napoli Federico II, via Pansini 5, 80129 Napoli, Italy
Dipto. di Genetica e Microbiologia, University of Pavia, Via Abbiategrasso 207, 27100 Pavia, Italy
Advanced Biotechnology Center, Department of Physics, University of Genova, Largo Rosanna Benzi, 10, 16132 Genova, Italy
References:
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Ascenzi, P., Amiconi, G., Bode, W., Bolognesi, M., Coletta, M., Menegatti, E., Proteinase inhibitors from the European medicinal leech Hirudo medicinalis: Structural functional and biomedical aspects (1995) Mol Aspects Med, 16, pp. 215-313
Banner, D.W., Hadvary, P., Crystallographic analysis at 30 Å resolution of the binding to human thrombin of four active site-directed inhibitors (1991) J Biol Chem, 266, pp. 20085-20093
Bar-Shavit, R., Kahn, A., Wilner, G.D., Mann, K.G., Fenton II, J.W., Localization of a chemotactic domain in human thrombin (1984) Biochemistry, 23, pp. 397-400
Berliner, L.J., (1992) Thrombin Structure and Function, , New York: Plenum Press
Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer Jr., E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Tasumi, M., The Protein Data Bank: A computer-based archival file for macromolecular structures (1977) J Mol Biol, 112, pp. 535-542
Bode, W., Huber, R., Natural protein proteinase inhibitors and their interaction with proteinases (1992) Eur J Biochem, 204, pp. 443-452
Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S.R., Hofsteenge, J., The refined 1.9 Å crystal structure of human α-thrombin: Interaction with D-Phe-Pro-Arg-chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment (1989) EMBO J, 8, pp. 3467-3475
Bode, W., Turk, D., Karshikov, A., The refined 1.9 Å X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human α-thrombin: Structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships (1992) Protein Sci, 1, pp. 426-471
Brandstetter, H., Turk, D., Hoeffken, H.W., Grosse, D., Stürzebecher, J., Martin, P.D., Edwards, B.F.P., Bode, W., Refined 2.3 Å X-ray crystal structure of bovine trombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP 4-TAPAP and MQPA (1992) J Mol Biol, 226, pp. 1085-1099
The CCP4 suite: Programs for protein crystallography (1994) Acta Crystallogr D, 50, pp. 760-767
Davie, E.W., Fujikawa, K., Kisiel, W., The coagulation cascade: Initiation maintenance and regulation (1991) Biochemistry, 30, pp. 10364-10370
DiMaio, J., Gibb, B., Munn, D., Lefebre, J., Ni, F., Konishi, Y., A new class of potent thrombin inhibitors that incorporates a scissile pseudopeptide bond (1991) FEBS Lett, 282, pp. 47-52
Engh, R.A., Huber, R., Accurate bond and angle parameters for X-ray protein structure refinement (1991) Acta Crystallogr A, 47, pp. 392-400
Engh, R.A., Brandstetter, H., Sucher, G., Eichinger, A., Baumann, U., Bode, W., Huber, R., Von Der Saal, W., Enzyme flexibility solvent and "weak" interactions characterize thrombin-ligand interactions: Implication for drug design (1996) Structure, 4, pp. 1353-1362
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Banner, D. W., Hadvary, P., Crystallographic analysis at 30 resolution of the binding to human thrombin of four active site-directed inhibitors (1991) J Biol Chem, 266, pp. 20085-20093
Berliner, L. J., (1992) Thrombin Structure and Function, , New York: Plenum Press
Bernstein, F. C., Koetzle, T. F., Williams, G. J. B., Meyer Jr., E. F., Brice, M. D., Rodgers, J. R., Kennard, O., Tasumi, M., The Protein Data Bank: A computer-based archival file for macromolecular structures (1977) J Mol Biol, 112, pp. 535-542
Davie, E. W., Fujikawa, K., Kisiel, W., The coagulation cascade: Initiation maintenance and regulation (1991) Biochemistry, 30, pp. 10364-10370
Engh, R. A., Huber, R., Accurate bond and angle parameters for X-ray protein structure refinement (1991) Acta Crystallogr A, 47, pp. 392-400
Engh, R. A., Brandstetter, H., Sucher, G., Eichinger, A., Baumann, U., Bode, W., Huber, R., Von Der Saal, W., Enzyme flexibility solvent and "weak" interactions characterize thrombin-ligand interactions: Implication for drug design (1996) Structure, 4, pp. 1353-1362
Fenton II, J. W., Thrombin (1986) Ann NY Acad Sci, 485, pp. 5-15
Fenton II, J. W., Bing, D. H., Thrombin active-site regions (1986) Semin Thromb Haemostasis, 12, pp. 200-208
Fenton II, J. W., Ofosu, F. A., Moon, D. G., Maraganore, J. M., Thrombin structure and function: Why thrombin is the primary target for antithrombotics (1991) Blood Coag Fibrinol, 2, pp. 69-75
F thi re, J., Tsuda, Y., Coulombe, R., Konishi, Y., Cygler, M., Crystal structure of two new bifunctional nonsubstrate type thrombin inhibitors complexed with human -thrombin (1996) Protein Sci, 5, pp. 1174-1183
Gr tter, M. G., Priestle, J. P., Rahuel, J., Grossenbacher, H., Bode, W., Hofsteenge, J., Stone, S. R., Crystal structure of the thrombin-hirudin complex: A novel mode of serine proteinase inhibition (1990) EMBO J, 9, pp. 2361-2365
Iwanowicz, E. J., Lau, W. F., Lin, J., Roberts, D. G. M., Seiler, S. M., Retro-binding tripeptide thrombin active-site inhibitors: Discovery synthesis and molecular modeling (1994) J Med Chem, 37, pp. 2122-2124
Jakubowski, J. A., Maraganore, J. M., Inhibition of coagulation and thrombin induced platelet activities by a synthetic dodecapeptide modeled on the carboxy terminus of hirudin (1990) Blood, 75, pp. 399-406
Jones, T. A., Zou, J. Y., Cowan, S., Kieldgaard, M., Improved methods for building protein models in electron density maps and location of errors in these models (1991) Acta Crystallogr A, 47, pp. 110-119
Krstenansky, J. L., Broersma, R. J., Owen, T. J., Payne, M. H., Yates, M. T., Mao, S. J., Development of MDL 28050 a small antithrombin agent based on a functional domain of the leech protein hirudin (1990) Thromb Haemostasis, 63, pp. 208-214
Leslie, A. G. W., (1992) Joint CCP4 and ESF-EACBM Newsletter on Protein Crystallography, 26. , Warrington, UK: Daresbury Laboratory
Malley, M. F., Tabernero, L., Chang, C. Y., Ohringer, S. L., Roberts, D. G. M., Das, J., Sack, J. S., Crystallographic determination of the structures of human -thrombin complexed with BMS-186282 and BMS-189090 (1996) Protein Sci, 5, pp. 221-228
Maraganore, J. M., Bourdon, P., Jablonski, J., Ramachandran, K. L., Fenton II, J. W., Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin (1990) Biochemistry, 29, pp. 7095-7101
Maryanoff, B. E., Qiu, X., Padmanabhan, K. P., Tulinsky, A., Almond Jr., H. R., Andrade-Gordon, P., Greco, M. N., Fusetani, N., Molecular basis for the inhibition of human -thrombin by the macrocyclic peptide cyclotheonamide A (1993) Proc Natl Acad Sci USA, 90, pp. 8048-8052
Mathews, I. I., Padmanabhan, K. P., Ganesh, V., Tulinsky, A., Isshii, M., Chen, J., Turck, C. W., Coughlin, S. R., Crystallographic structures of thrombin complexed with thrombin receptor peptides: Existence of expected and novel binding modes (1994) Biochemistry, 33, pp. 3266-3279
Rydel, T. J., Ravichandran, K. G., Tulinsky, A., Bode, W., Huber, R., Roitsch, C., Fenton, J. W., The structure of a complex of recombinant hirudin and human -thrombin (1990) Science, 249, pp. 277-280
Rydel, T. J., Tulinsky, A., Bode, W., Huber, R., Refined structure of the hirudin-thrombin complex (1991) J Mol Biol, 221, pp. 583-601
Salemme, F. R., Spurlino, J., Bone, R., Serendipity meets precision: The integration of structure-based drug design and combinatorial chemistry for efficient drug discovery (1997) Structure, 5, pp. 319-324
Stubbs, M. T., Bode, W., A player of many parts: The spotlight falls on thrombin's structure (1993) Thromb Res, 69, pp. 1-58
Stubbs, M. T., Oschkinat, H., Mayr, I., Huber, R., Angliker, H., Stone, S. R., Bode, W., The interaction of thrombin with fibrinogen. A structural basis for its specificity (1992) Eur J Biochem, 206, pp. 187-195
Stura, E. A., Wilson, I. A., Seeing techniques (1992) Crystallization of Nucleic Acids and Proteins: A Practical Approach, pp. 99-126. , Ducruix A, Gieg R, eds. Oxford, UK: Oxford University Press
Tollefsen, D. M., Feagler, J. R., Majerus, P. W., The binding of thrombin to the surface of human platelets (1974) J Biol Chem, 249, pp. 2646-2651
Vu, T. K. H., Wheaton, V. I., Hung, D. T., Charo, I., Coughlin, S. R., Domains specifying thrombin receptor interaction (1991) Nature, 353, pp. 674-677
Wu, T. P., Yee, V., Tulinsky, A., Chrusciel, R. A., Nakanashi, H., Shen, R., Priebe, C., Kahn, M., The structure of a designed peptidomimetic inhibitor complex of -thrombin (1993) Protein Eng, 6, pp. 471-478
Protein Sci (ISSN: 0961-8368, 1469-896xelectronic), 1998 Feb; 7(2): 243-253.
Export to BibTeX Export to EndNote
Paper type: Journal Article,
Impact factor: 4.44, 5-year impact factor: 3.602
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-0031890648&partnerID=40&md5=d81bc6e4a30626b70c66302ad4e6e62f
Keywords: Antithrombotics, Hirudin-Like Binding Mode, Hirunorms, Thrombin Synthetic Inhibitors, X-Ray Crystal Structure, Thrombin Inhibitor, Unclassified Drug, Article, Blood Clotting, Carboxy Terminal Sequence, Complex Formation, Crystallography, Human, Human Cell, Molecular Biology, Priority Journal, Protein Binding, Protein Interaction, Protein Structure, Antithrombins, Molecular Mimicry, Oligopeptides, Protein Conformation, Solvents,
Affiliations:
Ctro. Interuniversitario Ric. su P., Ctro. Stud. Biocristallografia - CNR, University of Napoli Federico II, via Mezzocannone 4, 80134 Napoli, Italy
Dipto. Biochim. Biotecnologie M., University of Napoli Federico II, via Pansini 5, 80129 Napoli, Italy
Dipto. di Genetica e Microbiologia, University of Pavia, Via Abbiategrasso 207, 27100 Pavia, Italy
Advanced Biotechnology Center, Department of Physics, University of Genova, Largo Rosanna Benzi, 10, 16132 Genova, Italy
References:
Abola, E.E., Bernstein, F.C., Bryant, S.H., Koetzle, T.F., Weng, J., Protein Data Bank (1987) Crystallographic Databases - Information Content, Software Systems, Scientific Applications, pp. 107-132. , Allen FH, Bergerhoff G, Sievers R, eds. Bonn/Cambridge/Chester: Data Commission of the International Union of Crystallograph
Ascenzi, P., Amiconi, G., Bode, W., Bolognesi, M., Coletta, M., Menegatti, E., Proteinase inhibitors from the European medicinal leech Hirudo medicinalis: Structural functional and biomedical aspects (1995) Mol Aspects Med, 16, pp. 215-313
Banner, D.W., Hadvary, P., Crystallographic analysis at 30 Å resolution of the binding to human thrombin of four active site-directed inhibitors (1991) J Biol Chem, 266, pp. 20085-20093
Bar-Shavit, R., Kahn, A., Wilner, G.D., Mann, K.G., Fenton II, J.W., Localization of a chemotactic domain in human thrombin (1984) Biochemistry, 23, pp. 397-400
Berliner, L.J., (1992) Thrombin Structure and Function, , New York: Plenum Press
Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer Jr., E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Tasumi, M., The Protein Data Bank: A computer-based archival file for macromolecular structures (1977) J Mol Biol, 112, pp. 535-542
Bode, W., Huber, R., Natural protein proteinase inhibitors and their interaction with proteinases (1992) Eur J Biochem, 204, pp. 443-452
Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S.R., Hofsteenge, J., The refined 1.9 Å crystal structure of human α-thrombin: Interaction with D-Phe-Pro-Arg-chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment (1989) EMBO J, 8, pp. 3467-3475
Bode, W., Turk, D., Karshikov, A., The refined 1.9 Å X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human α-thrombin: Structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships (1992) Protein Sci, 1, pp. 426-471
Brandstetter, H., Turk, D., Hoeffken, H.W., Grosse, D., Stürzebecher, J., Martin, P.D., Edwards, B.F.P., Bode, W., Refined 2.3 Å X-ray crystal structure of bovine trombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP 4-TAPAP and MQPA (1992) J Mol Biol, 226, pp. 1085-1099
The CCP4 suite: Programs for protein crystallography (1994) Acta Crystallogr D, 50, pp. 760-767
Davie, E.W., Fujikawa, K., Kisiel, W., The coagulation cascade: Initiation maintenance and regulation (1991) Biochemistry, 30, pp. 10364-10370
DiMaio, J., Gibb, B., Munn, D., Lefebre, J., Ni, F., Konishi, Y., A new class of potent thrombin inhibitors that incorporates a scissile pseudopeptide bond (1991) FEBS Lett, 282, pp. 47-52
Engh, R.A., Huber, R., Accurate bond and angle parameters for X-ray protein structure refinement (1991) Acta Crystallogr A, 47, pp. 392-400
Engh, R.A., Brandstetter, H., Sucher, G., Eichinger, A., Baumann, U., Bode, W., Huber, R., Von Der Saal, W., Enzyme flexibility solvent and "weak" interactions characterize thrombin-ligand interactions: Implication for drug design (1996) Structure, 4, pp. 1353-1362
Fenton II, J.W., Thrombin (1986) Ann NY Acad Sci, 485, pp. 5-15
Fenton II, J.W., Bing, D.H., Thrombin active-site regions (1986) Semin Thromb Haemostasis, 12, pp. 200-208
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Rydel, T. J., Tulinsky, A., Bode, W., Huber, R., Refined structure of the hirudin-thrombin complex (1991) J Mol Biol, 221, pp. 583-601
Salemme, F. R., Spurlino, J., Bone, R., Serendipity meets precision: The integration of structure-based drug design and combinatorial chemistry for efficient drug discovery (1997) Structure, 5, pp. 319-324
Stubbs, M. T., Bode, W., A player of many parts: The spotlight falls on thrombin's structure (1993) Thromb Res, 69, pp. 1-58
Stubbs, M. T., Oschkinat, H., Mayr, I., Huber, R., Angliker, H., Stone, S. R., Bode, W., The interaction of thrombin with fibrinogen. A structural basis for its specificity (1992) Eur J Biochem, 206, pp. 187-195
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Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex
A novel class of synthetic, multisite-directed thrombin inhibitors, known as hirunorms, has been described recently. These compounds were designed to mimic the binding mode of hirudin, and they have been proven to be very strong and selective thrombin inhibitors. Here we report the crystal structure of the complex formed by human a-thrombin and hirunorm V, a 26-residue polypeptide containing non-natural amino acids, determined at 2. 1 Angstrom resolution and refined to an R-factor of 0. 176. The structure reveals that the inhibitor binding mode is distinctive of a true hirudin mimetic, and it highlights the molecular basis of the high inhibitory potency (K-i is in the picomolar range) and the strong selectivity of hirunorm V. Hirunorm V interacts through the N-terminal tetrapeptide with the thrombin active site in a nonsubstrate mode; at the same time, this inhibitor specifically binds through the C-terminal segment to the fibrinogen recognition exosite, The backbone of the N-terminal tetrapeptide Chg (1) "-Val (2) "-2-Nal (3) "-Thr (4) " (Chg, cyclohexyl-glycine; 2-Nal, beta- (2-naphthyl) -alanine) forms a short beta-strand parallel to thrombin main-chain residues Ser (214) -Gly (219). The Chg (1) " side chain fills the S2 subsite, Val (2) " is located at the entrance of S1, whereas 2-Nal (3) " side chain occupies the aryl-binding site. Such backbone orientation is very close to that observed for the N-terminal residues of hirudin, and it is similar to that of the synthetic retro-binding peptide BMS-183507, but it is opposite to the proposed binding mode of fibrinogen and of small synthetic substrates. Hirunorm V C-terminal segment binds to the fibrinogen recognition exosite, similarly to what observed for hirudin C-terminal tail and related compounds. The linker polypeptide segment connecting hirunorm V Nand C-terminal regions is not observable in the electron density maps. The crystallographic analysis proves the correctness of the design and it provides a compelling proof on the interaction mechanism for this novel class of high potency multisite-directed synthetic thrombin inhibitors
A novel class of synthetic, multisite-directed thrombin inhibitors, known as hirunorms, has been described recently. These compounds were designed to mimic the binding mode of hirudin, and they have been proven to be very strong and selective thrombin inhibitors. Here we report the crystal structure of the complex formed by human a-thrombin and hirunorm V, a 26-residue polypeptide containing non-natural amino acids, determined at 2. 1 Angstrom resolution and refined to an R-factor of 0. 176. The structure reveals that the inhibitor binding mode is distinctive of a true hirudin mimetic, and it highlights the molecular basis of the high inhibitory potency (K-i is in the picomolar range) and the strong selectivity of hirunorm V. Hirunorm V interacts through the N-terminal tetrapeptide with the thrombin active site in a nonsubstrate mode; at the same time, this inhibitor specifically binds through the C-terminal segment to the fibrinogen recognition exosite, The backbone of the N-terminal tetrapeptide Chg (1) "-Val (2) "-2-Nal (3) "-Thr (4) " (Chg, cyclohexyl-glycine; 2-Nal, beta- (2-naphthyl) -alanine) forms a short beta-strand parallel to thrombin main-chain residues Ser (214) -Gly (219). The Chg (1) " side chain fills the S2 subsite, Val (2) " is located at the entrance of S1, whereas 2-Nal (3) " side chain occupies the aryl-binding site. Such backbone orientation is very close to that observed for the N-terminal residues of hirudin, and it is similar to that of the synthetic retro-binding peptide BMS-183507, but it is opposite to the proposed binding mode of fibrinogen and of small synthetic substrates. Hirunorm V C-terminal segment binds to the fibrinogen recognition exosite, similarly to what observed for hirudin C-terminal tail and related compounds. The linker polypeptide segment connecting hirunorm V Nand C-terminal regions is not observable in the electron density maps. The crystallographic analysis proves the correctness of the design and it provides a compelling proof on the interaction mechanism for this novel class of high potency multisite-directed synthetic thrombin inhibitors
Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex
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Hirunorms Are True Hirudin Mimetics. The Crystal Structure Of Human Alpha-Thrombin-Hirunorm V Complex
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De Simone G, Bua S, Supuran CT, Alterio V
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Impact Factor: 2.531
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Di Fiore A, De Simone G, Menchise V, Pedone C, Casini A, Scozzafava A, Supuran CT
* Carbonic anhydrase inhibitors: X-ray crystal structure of a benzenesulfonamide strong CA II and CA IX inhibitor bearing a pentafluorophenylaminothioureido tail in complex with isozyme II (489 views)
Bioorg Med Chem Lett Bioorganic And Medicinal Chemistry Letters (ISSN: 0960-894x), 2005 Apr 1; 15(7): 1937-1942.
Impact Factor: 2.478
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De Simone G, Menchise V, Omaggio S, Pedone C, Scozzafava A, Supuran CT
* Design of weakly basic thrombin inhibitors incorporating novel P1 binding functions: Molecular and X-ray crystallographic studies (353 views)
Biochemistry (ISSN: 0006-2960, 1520-4995, 1520-4995electronic), 2003 Sep 5; 42(30): 9013-9021.
Impact Factor: 3.922
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Lombardi A, De Simone G, Nastri F, Galdiero S, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V
The Crystal Structure Of Alpha-Thrombin-Hirunorm Iv Complex Reveals A Novel Specificity Site Recognition Mode (428 views)
Protein Sci (ISSN: 0961-8368, 1469-896xelectronic), 1999 Jan; 8(1): 91-95.
Impact Factor: 4.457
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Lombardi A, De Simone G, Galdiero S, Staiano N, Nastri F, Pavone V
From natural to synthetic multisite thrombin inhibitors (349 views)
Biopolymers (ISSN: 0006-3525, 0006-6352, 0006-3525print), 1999; 51(1): 19-39.
Impact Factor: 2.331
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Pavone V, De Simone G, Nastri F, Galdiero S, Staiano N, Lombardi A, Pedone C
Multiple binding mode of reversible synthetic thrombin inhibitors. A comparative structural analysis (589 views)
Biol Chem Biological Chemistry (ISSN: 1431-6730, 1437-4315), 1998 Sep; 379(8-9): 987-1006.
Impact Factor: 2.636
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Pavone V, Lombardi A, Saviano M, Di Blasio B, Nastri F, Fattorusso R, Zaccaro L, Maglio O, Yamada T, Omote Y
Mixed conformation in C(α, α)-disubstituted tripeptides: X-ray crystal structures of Z-Aib-Dph-Gly-OMe and Bz-Dph-Dph-Gly-OMe (400 views)
Biopolymers (ISSN: 0006-3525, 0006-6352, 0006-3525print), 1994 Dec; 34(12): 1595-1604.
Impact Factor: 2.425
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10 Records (10 excluding Abstracts).
Total impact factor: 30.643 (30.643 excluding Abstracts).
Total 5 year impact factor: 29.672 (29.672 excluding Abstracts).
Total impact factor: 30.643 (30.643 excluding Abstracts).
Total 5 year impact factor: 29.672 (29.672 excluding Abstracts).
520 views. Last view on Friday 24 March 2023, 14:22:33
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