Chapter 5 1 protein function reversible binding of protein to a ligand
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Chapter 5.1: Protein Function - Reversible Binding of Protein to a Ligand. CHEM 7784 Biochemistry Professor Bensley. CHAPTER 5.1 Reversible Binding of Protein to a Ligand. Reversible binding of ligands Structure of myoglobin and hemoglobin Origin of cooperativity in hemoglobin.

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Chapter 5.1: Protein Function - Reversible Binding of Protein to a Ligand

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Chapter 5 1 protein function reversible binding of protein to a ligand

Chapter 5.1: Protein Function - Reversible Binding of Protein to a Ligand

CHEM 7784

Biochemistry

Professor Bensley


Chapter 5 1 reversible binding of protein to a ligand

CHAPTER 5.1Reversible Binding of Protein to a Ligand

  • Reversible binding of ligands

  • Structure of myoglobin and hemoglobin

  • Origin of cooperativity in hemoglobin

Today’s Objectives - To learn and understand:


Functions of globular proteins

Functions of Globular Proteins

  • Storage of ions and molecules

    • myoglobin, ferritin

  • Transport of ions and molecules

    • hemoglobin, serotonin transporter

  • Defense against pathogens

    • antibodies, cytokines

  • Muscle contraction

    • actin, myosin

  • Biological catalysis

    • chymotrypsin, lysozyme


Binding quantitative description

Binding: Quantitative Description

  • Consider a process in which a ligand (L) binds reversibly to a site in the protein (P)

  • The equilibrium composition is characterized by the equilibrium constant Ka

ka

+

L

PL

P

kd


Binding analysis in terms of the bound fraction

Binding: Analysis in Terms of the Bound Fraction

  • In practice, we can often determine the fraction of occupied binding sites

  • Substituting [PL] with Ka[L][P], we’ll eliminate [PL]

  • Eliminating [P] and rearranging gives the result in terms of equilibrium association constant:

  • In terms of the more commonly used equilibrium dissociation constant:


Binding graphical analysis

Binding: Graphical Analysis

  • The fraction of bound sites depends on the free ligand concentration and Kd

  • In a typical experiment, ligand concentration is the known independent variable

  • Kd can be determined graphically or via least-squares regression

[L]  [L]total


Specificity lock and key model

Specificity: Lock-and-Key Model

  • “Lock and Key” model by Emil Fischer (1894) assumes that complementary surfaces are preformed.

+


Specificity induced fit

Specificity: Induced Fit

  • Conformational changes may occur upon ligand binding (Daniel Koshland in 1958).

    • This adaptation is called the inducedfit.

    • Induced fit allows for tighter binding of the ligand

    • Induced fit can increase the affinity of the protein for a second ligand

  • Both the ligand and the protein can change their conformations

+


Myoglobin hemoglobin

Myoglobin/Hemoglobin

  • First protein structures determined

  • Oxygen carriers

  • Hemoglobin: transportsO2 from lungs to tissues

  • Myoglobin: O2storage protein


Mb and hb subunits structurally similar

Mb and Hb Subunits Structurally Similar

  • 8 alpha-helices

  • Contain heme group

  • Mb monomeric protein

  • Hbheterotetramer (α2β2)

myoglobin

hemoglobin


Heme group

Heme Group


Structure of myoglobin

Structure of Myoglobin


Hemoglobin

Hemoglobin


Oxygen binding curves

Oxygen Binding Curves

  • Mb has hyberbolic O2 binding curve

  • Mb binds O2 tightly. Releases at very low pO2

  • Hb has sigmoidal O2 binding curve

  • Hb high affinity for O2 at high pO2 (lungs)

  • Hb low affinity for O2 at low pO2 (tissues)


Oxygen binding curve

Oxygen Binding Curve


Oxygen binding curve1

Oxygen Binding Curve


O 2 binding to hb shows positive cooperativity

O2 Binding to Hb shows Positive Cooperativity

  • Hb binds four O2 molecules

  • O2 affinity increases as each O2 molecule binds

  • Increased affinity due to conformation change

  • Deoxygenated form = T (tense) form = low affinity

  • Oxygenated form = R (relaxed) form = high affinity


O 2 binding to hb shows positive cooperativity1

O2 Binding to Hb shows Positive Cooperativity


Conformational change is triggered by oxygen binding

Conformational Change is Triggered by Oxygen Binding


Chapter 5 1 protein function reversible binding of protein to a ligand

Video on Hemoglobin


Allosteric interactions

Allosteric Interactions

  • Allosteric interaction occurs when specific molecules bind a protein and modulate activity

  • Allosteric modulators or allosteric effectors

  • Bind reversibly to site separate from functional binding or active site

  • Modulation of activity occurs through change in protein conformation

  • 2,3 bisphosphoglycerate (BPG), CO2 and protons are allosteric effectors of Hb binding of O2


Regulation of o 2 binding by 2 3 bisphospho glycerate

Regulation of O2 Binding by 2,3-Bisphospho-glycerate


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