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Visualizing the Structure and Function of Integral Membrane Proteins C. Watters 1, D. Guertin 2, D....
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Transcript of Visualizing the Structure and Function of Integral Membrane Proteins C. Watters 1, D. Guertin 2, D....
![Page 1: Visualizing the Structure and Function of Integral Membrane Proteins C. Watters 1, D. Guertin 2, D. Conache 2, and D. Koparov 2 Department of Biology 1.](https://reader036.fdocuments.in/reader036/viewer/2022070403/56649f295503460f94c42c21/html5/thumbnails/1.jpg)
Visualizing the Structure and Function of Integral
Membrane Proteins
C. Watters1, D. Guertin2, D. Conache2, and D. Koparov2
Department of Biology1 and Library
and Informational Services2,
Middlebury College5 July 2005
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Watters, et al., 2005, Middlebury College 2
Introduction & Goals
Create dynamic models of integral membrane proteins (IMP).
Integrate functional and structural aspects of IMP simply but accurately.
Render IMP behavior in a stochastic manner.
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Watters, et al., 2005, Middlebury College 3
The Na+/K+ Pump: A Case in Point
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Watters, et al., 2005, Middlebury College 4
The Post-Albers Model of the Na+/K+ Pump
![Page 5: Visualizing the Structure and Function of Integral Membrane Proteins C. Watters 1, D. Guertin 2, D. Conache 2, and D. Koparov 2 Department of Biology 1.](https://reader036.fdocuments.in/reader036/viewer/2022070403/56649f295503460f94c42c21/html5/thumbnails/5.jpg)
Watters, et al., 2005, Middlebury College 5
Pump Structure and Function: A Static Cartoon
![Page 6: Visualizing the Structure and Function of Integral Membrane Proteins C. Watters 1, D. Guertin 2, D. Conache 2, and D. Koparov 2 Department of Biology 1.](https://reader036.fdocuments.in/reader036/viewer/2022070403/56649f295503460f94c42c21/html5/thumbnails/6.jpg)
Watters, et al., 2005, Middlebury College 6
The Calcium Pump
E1 State E2 State
(from PDB, after Toyoshima, et al., 2000; Xu, et al., 2002)
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Watters, et al., 2005, Middlebury College 7
Conservation of Pump Structures
Na+/K+ Pump Ca2+ Pump
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Watters, et al., 2005, Middlebury College 8
E1 Structure
Nucleotide- (N) and Phosphate- (P) binding domains separated from Activation (A) domain.
Helical membrane domains (M) open to cytoplasm; “Na+ sticky”.
ATP bound to N domain.
![Page 9: Visualizing the Structure and Function of Integral Membrane Proteins C. Watters 1, D. Guertin 2, D. Conache 2, and D. Koparov 2 Department of Biology 1.](https://reader036.fdocuments.in/reader036/viewer/2022070403/56649f295503460f94c42c21/html5/thumbnails/9.jpg)
Watters, et al., 2005, Middlebury College 9
E2 Structure
P, N, A domains associated, forming active catalytic unit.
Helical membrane domains open to exterior; “K+ sticky”.
ATP hydrolyzed: ADP released; P domain phosphorylated.
![Page 10: Visualizing the Structure and Function of Integral Membrane Proteins C. Watters 1, D. Guertin 2, D. Conache 2, and D. Koparov 2 Department of Biology 1.](https://reader036.fdocuments.in/reader036/viewer/2022070403/56649f295503460f94c42c21/html5/thumbnails/10.jpg)
Watters, et al., 2005, Middlebury College 10
Creating A Domain StructureDrawing splines and “skinning” the ATP-binding domain (N) using LightWave 3D.
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Watters, et al., 2005, Middlebury College 11
Assembled ATPase of the Na+/K+ Pump
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Watters, et al., 2005, Middlebury College 12
Na+/K+ Pump(subunit)
E1 E2
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Watters, et al., 2005, Middlebury College 13
Placing the Pump in a Membrane Perspective
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14Watters, et al., 2005, Middlebury College
The Na+/K+ Pump.
THE MOVIESTHE MOVIESPumping Ions 1PI 2. Ouabain’s Revenge: the Pump HaltedPI 3. Pump Redux, or Overwhelmed by the
Gradients.
PI 4. The Great Na+ - Na+ Exchange PI 5. The Great K+ - K+ Exchange
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Watters, et al., 2005, Middlebury College 15
Limitations of Pump Models
Crystallographic structures may not be accurate “native” structures.
Organization of transmembrane helical domain is inaccurate. Helices not parallel; no “channel” evident.Binding sites may not be arranged as depicted.Na+- and K+-binding sites may be different: likely overlapping.Cooperative effects of N, P and A domains (= catalysis) on transmembrane domain likely more complex than shown.
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Watters, et al., 2005, Middlebury College 16
Other Integral Membrane Proteins: Tyrosine Kinase and G-protein-linked
Hormone Receptors
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Watters, et al., 2005, Middlebury College 17
Tyrosine Kinase ReceptorsInitial Events: EGF Binding to EGFR
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Watters, et al., 2005, Middlebury College 18
Tyrosine Kinase ReceptorsDownstream Transduction Events
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Watters, et al., 2005, Middlebury College 19
Tyrosine Kinase ReceptorsKinase Inhibition by 4-Anilinolquinazoline
David –put PDB 1M17Here, to sameScale, highlighting inhibitor.
EGFR - Kinase Domain
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Watters, et al., 2005, Middlebury College 20
Other Integral Membrane Proteins: Signaling by Tyrosine Kinase and G-protein-
linked Hormone Receptors
David: provide link from each still to a QT movie.
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Watters, et al., 2005, Middlebury College 21
Acknowledgments
Middlebury College:
Information and Library Services.
Professional Development Fund provided by the Irene Heinz and John LaPorte Given Professorship in Premedical Sciences.