[Frontiers in Bioscience 9, 3486-3509, September 1, 2004] 3486 DEVELOPMENT OF NEW ANTI-CANCER PEPTIDES FROM CONFORMATIONAL ENERGY ANALYSIS OF THE ONCOGENIC ras-P21 PROTEIN AND ITS COMPLEXES WITH TARGET PROTEINS

1. Abstract 2. Introduction 2.1. Mutated proteins can induce malignant transformation 2.2. Mutant ras-p21 Protein Is a Major Cause of Cancer 2.3. ras-induced signal transduction pathways 2.4. Direct interactions between ras-p21 and target proteins depends largely on two of its domains 2.5. How amino acid substitutions in ras-p21 can induce it to become oncogenic 3. Methods 3.1. Computational methods 3.1.1. Basic aim 3.1.2. Overall methodology 3.1.3. Proteins studied 3.1.4. Generation of starting structures 3.2. Materials and methods 3.2.1. Proteins 3.2.2 Peptides 3.2.3. c-DNA 3.2.4. Plasmids 3.2.5. Oocyte microinjection 3.2.6. Cells 4. Results and Discussion 4.1. Conformational analysis of wild-type and oncogenic ras-p21 4.1.1. Peptides that block oncogenic ras-p21 selectively 4.1.2 Peptides that selectively block oncogenic ras-p21 in oocytes block tumor cell growth 4.1.3 Oncogenic and activated normal ras-p21 proteins utilize divergent signal transduction pathways 4.1.4 Critical targets of oncogenic ras-p21 4.1.5 The raf-MEK-MAP kinase pathway is also critical for oncogenic ras-p21 4.2. Conformational analysis of wild-type and oncogenic ras-p21 bound to target proteins 4.2.1.Calculations reveal new peptide domains in ras-p21 targets involved in cell signaling 4.2.2. Interpretation of results 4.2.3. ras-p21raf RBD complexes 4.2.3.1 RBD peptides block ras signaling 4.2.3.2. The RBD 97-110 domain peptide blocks oncogenic ras-p21 selectively 4.2.3.3. How the ras-p21 35-47 peptide might block oncogenic ras-p21 selectively 4.2.3.4. Conclusions 4.2.4. ras-p21-SOS complex 4.2.4.1. Results of molecular dynamics calculations on ras-p21-SOS complexes 4.2.4.2 SOS domain peptides block ras-p21-induced signal transduction 4.2.4.3 Specificity of inhibition 4.2.4.4.Conclusions 4.2.5. ras-p21 GAP structures 4.2.5.1 Results of molecular dynamics calculations on ras-p21-GAP complexes 4.2.5.2 GAP domain peptides inhibit ras-p21 signaling 4.2.5.3 Conclusions 4.3. Dynamics calculations on GST-pi, a specific JNK-jun inhibitor 5. Conclusions 6. Acknowledgements 7. References