CHAPTER 1 From Sequence to Structure
1-0 Overview: Protein Function and Architecture ................ 2
1-1 Amino Acids ................................................ 4
1-2 Genes and Proteins ......................................... 6
1-3 The Peptide Bond ........................................... 8
1-4 Bonds that Stabilize Folded Proteins ...................... 10
1-5 Importance and Determinants of Secondary Structure ........ 12
1-6 Properties of the Alpha Helix ............................. 14
1-7 Properties of the Beta Sheet .............................. 16
1-8 Prediction of Secondary Structure ......................... 18
1-9 Folding ................................................... 20
1-10 Tertiary Structure ........................................ 22
1-11 Membrane Protein Structure ................................ 24
1-12 Protein Stability: Weak Interactions and Flexibility ...... 26
1-13 Protein Stability: Post-Translational Modifications ....... 28
1-14 The Protein Domain ........................................ 30
1-15 The Universe of Protein Structures ........................ 32
1-16 Protein Motifs ............................................ 34
1-17 Alpha Domains and Beta Domains ............................ 36
1-18 Alpha/Beta, Alpha+Beta and Cross-Linked Domains ........... 38
1-19 Quaternary Structure: General Principles .................. 40
1-20 Quaternary Structure: Intermolecular Interfaces ........... 42
1-21 Quaternary Structure: Geometry ............................ 44
1-22 Protein Flexibility ....................................... 46
CHAPTER 2 From Structure to Function
2-0 Overview: The Structural Basis of Protein Function ........ 50
2-1 Recognition, Complementarity and Active Sites ............. 52
2-2 Flexibility and Protein Function .......................... 54
2-3 Location of Binding Sites ................................. 56
2-4 Nature of Binding Sites ................................... 58
2-5 Functional Properties of Structural Proteins .............. 60
2-6 Catalysis: Overview ....................................... 62
2-7 Active-Site Geometry ...................................... 64
2-8 Proximity and Ground-State Destabilization ................ 66
2-9 Stabilization of Transition States and Exclusion of
Water ..................................................... 68
2-10 Redox Reactions ........................................... 70
2-11 Addition/Elimination, Hydrolysis and Decarboxylation ...... 72
2-12 Active-Site Chemistry ..................................... 74
2-13 Cofactors ................................................. 76
2-14 Multi-Step Reactions ...................................... 78
2-15 Multifunctional Enzymes ................................... 80
2-16 Multifunctional Enzymes with Tunnels ...................... 82
CHAPTER 3 Control of Protein Function
3-0 Overview: Mechanisms of Regulation ........................ 86
3-1 Protein Interaction Domains ............................... 88
3-2 Regulation by Location .................................... 90
3-3 Control by pH and Redox Environment ....................... 92
3-4 Effector Ligands: Competitive Binding and Cooperativity ... 94
3-5 Effector Ligands: Conformational Change and Allostery ..... 96
3-6 Protein Switches Based on Nucleotide Hydrolysis ........... 98
3-7 GTPase Switches: Small Signaling G proteins .............. 100
3-8 GTPase Switches: Signal Relay by Heterotrimeric
GTPases .................................................. 102
3-9 GTPase Switches: Protein Synthesis ....................... 104
3-10 Motor Protein Switches ................................... 106
3-11 Regulation by Degradation ................................ 108
3-12 Control of Protein Function by Phosphorylation ........... 110
3-13 Regulation of Signaling Protein Kinases: Activation
Mechanism ................................................ 112
3-14 Regulation of Signaling Protein Kinases: Cdk
Activation ............................................... 114
3-15 Two-Component Signaling Systems in Bacteria .............. 116
3-16 Control by Proteolysis: Activation of Precursors ......... 118
3-17 Protein Splicing: Autoproteolysis by Inteins ............. 120
3-18 Glycosylation ............................................ 122
3-19 Protein Targeting by Lipid Modifications ................. 124
3-20 Methylation, N-acetylation, Sumoylation and
Nitrosylation ............................................ 126
CHAPTER 4 From Sequence to Function: Case Studies in
Structural and Functional Genomics
4-0 Overview: From Sequence to Function in the Age of
Genomics ................................................. 130
4-1 Sequence Alignment and Comparison ........................ 132
4-2 Protein Profiling ........................................ 134
4-3 Deriving Function from Sequence .......................... 136
4-4 Experimental Tools for Probing Protein Function .......... 138
4-5 Divergent and Convergent Evolution ....................... 140
4-6 Structure from Sequence: Homology Modeling ............... 142
4-7 Structure From Sequence: Profile-Based Threading and
"Rosetta" ................................................ 144
4-8 Deducing Function from Structure: Protein
Superfamilies ............................................ 146
4-9 Strategies for Identifying Binding Sites ................. 148
4-10 Strategies for Identifying Catalytic Residues ............ 150
4-11 TIM Barrels: One Structure with Diverse Functions ........ 152
4-12 PLP Enzymes: Diverse Structures with One Function ........ 154
4-13 Moonlighting: Proteins With More Than One Function ....... 156
4-14 Chameleon Sequences: One Sequence with More than One
Fold ..................................................... 158
4-15 Prions, Amyloids and Serpins: Metastable Protein Folds ... 160
4-16 Functions for Uncharacterized Genes: Galactonate
Dehydratase .............................................. 162
4-17 Starting From Scratch: A Gene Product of Unknown
Function ................................................. 164
CHAPTER 5 Structure Determination
5-1 The Interpretation of Structural Information ............. 168
5-2 Structure Determination by X-Ray Crystallography
and NMR .................................................. 170
5-3 Quality and Representation of Crystal and NMR
Structures ............................................... 172
Glossary ...................................................... 175
References .................................................... 181
Index ......................................................... 189
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