Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery

Deborah K Shoemark; Christopher Williams; Mark S Fahey; Judy J Watson; Sue J Tyler; Simon J Scoltock; Rosamund Ellis; Elaine  Wickendon; Antony J Burton; Jennifer Luise L Hemmings; Christopher D Bailey; David Dawbarn; David E Jane; Chris L Willis; Richard B Sessions; Shelley J Allen; Matthew P Crump

doi:10.1021/jm501307e

Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery

Deborah K Shoemark
, Christopher Williams
, Mark S Fahey
, Judy J Watson
, Sue J Tyler
, Simon J Scoltock
, Rosamund Ellis
, Elaine Wickendon
, Antony J Burton
, Jennifer Luise L Hemmings
, Christopher D Bailey
, David Dawbarn
, David E Jane
, Chris L Willis
, Richard B Sessions
, Shelley J Allen ^*
, Matthew P Crump

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

11 Citations (Scopus)

373 Downloads (Pure)

Abstract

The tyrosine kinase A (TrkA) receptor is a validated therapeutic intervention point for a wide range of conditions. TrkA activation by nerve growth factor (NGF) binding the second extracellular immunoglobulin (TrkAIg2) domain, triggers intracellular signalling cascades. In the periphery this promotes the pain phenotype and in the brain, cell survival or differentiation.
Reproducible structural information and detailed validation of protein-ligand interactions aid drug discovery. However, the isolated TrkAIg2 domain crystallizes as a β-strand-swapped dimer in the absence of NGF, occluding the binding surface. Here we report the design and structural validation by nuclear magnetic resonance spectroscopy of the first stable, biologically active construct of the TrkAIg2 domain for binding-site confirmation. Our structure closely mimics the wild-type fold of TrkAIg2 in complex with NGF (1WWW.pdb)
and the 1H-15N correlation spectra confirm that both NGF and a competing small molecule, interact at the known binding interface in solution.

Original language	English
Pages (from-to)	767-777
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	2
Early online date	2 Dec 2014
DOIs	https://doi.org/10.1021/jm501307e
Publication status	Published - 22 Jan 2015

Research Groups and Themes

BCS and TECS CDTs
Cerebrovascular and Dementia Research Group
Organic & Biological

Keywords

TrkA, TrkAIg2, drug discovery, NMR construct, pain, Alzheimer’s

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10.1021/jm501307e

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Shoemark, D. K., Williams, C., Fahey, M. S., Watson, J. J., Tyler, S. J., Scoltock, S. J., Ellis, R., Wickendon, E., Burton, A. J., Hemmings, J. L. L., Bailey, C. D., Dawbarn, D., Jane, D. E., Willis, C. L., Sessions, R. B., Allen , S. J., & Crump, M. P. (2015). Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery. Journal of Medicinal Chemistry, 58(2), 767-777. https://doi.org/10.1021/jm501307e

@article{ef88c645344d43d5af1569ecf8224f68,

title = "Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery",

abstract = "The tyrosine kinase A (TrkA) receptor is a validated therapeutic intervention point for a wide range of conditions. TrkA activation by nerve growth factor (NGF) binding the second extracellular immunoglobulin (TrkAIg2) domain, triggers intracellular signalling cascades. In the periphery this promotes the pain phenotype and in the brain, cell survival or differentiation. Reproducible structural information and detailed validation of protein-ligand interactions aid drug discovery. However, the isolated TrkAIg2 domain crystallizes as a β-strand-swapped dimer in the absence of NGF, occluding the binding surface. Here we report the design and structural validation by nuclear magnetic resonance spectroscopy of the first stable, biologically active construct of the TrkAIg2 domain for binding-site confirmation. Our structure closely mimics the wild-type fold of TrkAIg2 in complex with NGF (1WWW.pdb) and the 1H-15N correlation spectra confirm that both NGF and a competing small molecule, interact at the known binding interface in solution. ",

keywords = "TrkA, TrkAIg2, drug discovery, NMR construct, pain, Alzheimer{\textquoteright}s",

author = "Shoemark, \{Deborah K\} and Christopher Williams and Fahey, \{Mark S\} and Watson, \{Judy J\} and Tyler, \{Sue J\} and Scoltock, \{Simon J\} and Rosamund Ellis and Elaine Wickendon and Burton, \{Antony J\} and Hemmings, \{Jennifer Luise L\} and Bailey, \{Christopher D\} and David Dawbarn and Jane, \{David E\} and Willis, \{Chris L\} and Sessions, \{Richard B\} and Allen, \{Shelley J\} and Crump, \{Matthew P\}",

year = "2015",

month = jan,

day = "22",

doi = "10.1021/jm501307e",

language = "English",

volume = "58",

pages = "767--777",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "2",

}

Shoemark, DK , Williams, C, Fahey, MS, Watson, JJ, Tyler, SJ, Scoltock, SJ, Ellis, R, Wickendon, E, Burton, AJ, Hemmings, JLL, Bailey, CD, Dawbarn, D, Jane, DE, Willis, CL , Sessions, RB, Allen , SJ & Crump, MP 2015, 'Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery', Journal of Medicinal Chemistry, vol. 58, no. 2, pp. 767-777. https://doi.org/10.1021/jm501307e

Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery. / Shoemark, Deborah K ; Williams, Christopher; Fahey, Mark S et al.
In: Journal of Medicinal Chemistry, Vol. 58, No. 2, 22.01.2015, p. 767-777.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery

AU - Shoemark, Deborah K

AU - Williams, Christopher

AU - Fahey, Mark S

AU - Watson, Judy J

AU - Tyler, Sue J

AU - Scoltock, Simon J

AU - Ellis, Rosamund

AU - Wickendon, Elaine

AU - Burton, Antony J

AU - Hemmings, Jennifer Luise L

AU - Bailey, Christopher D

AU - Dawbarn, David

AU - Jane, David E

AU - Willis, Chris L

AU - Sessions, Richard B

AU - Allen , Shelley J

AU - Crump, Matthew P

PY - 2015/1/22

Y1 - 2015/1/22

N2 - The tyrosine kinase A (TrkA) receptor is a validated therapeutic intervention point for a wide range of conditions. TrkA activation by nerve growth factor (NGF) binding the second extracellular immunoglobulin (TrkAIg2) domain, triggers intracellular signalling cascades. In the periphery this promotes the pain phenotype and in the brain, cell survival or differentiation. Reproducible structural information and detailed validation of protein-ligand interactions aid drug discovery. However, the isolated TrkAIg2 domain crystallizes as a β-strand-swapped dimer in the absence of NGF, occluding the binding surface. Here we report the design and structural validation by nuclear magnetic resonance spectroscopy of the first stable, biologically active construct of the TrkAIg2 domain for binding-site confirmation. Our structure closely mimics the wild-type fold of TrkAIg2 in complex with NGF (1WWW.pdb) and the 1H-15N correlation spectra confirm that both NGF and a competing small molecule, interact at the known binding interface in solution.

AB - The tyrosine kinase A (TrkA) receptor is a validated therapeutic intervention point for a wide range of conditions. TrkA activation by nerve growth factor (NGF) binding the second extracellular immunoglobulin (TrkAIg2) domain, triggers intracellular signalling cascades. In the periphery this promotes the pain phenotype and in the brain, cell survival or differentiation. Reproducible structural information and detailed validation of protein-ligand interactions aid drug discovery. However, the isolated TrkAIg2 domain crystallizes as a β-strand-swapped dimer in the absence of NGF, occluding the binding surface. Here we report the design and structural validation by nuclear magnetic resonance spectroscopy of the first stable, biologically active construct of the TrkAIg2 domain for binding-site confirmation. Our structure closely mimics the wild-type fold of TrkAIg2 in complex with NGF (1WWW.pdb) and the 1H-15N correlation spectra confirm that both NGF and a competing small molecule, interact at the known binding interface in solution.

KW - TrkA, TrkAIg2, drug discovery, NMR construct, pain, Alzheimer’s

UR - https://www.scopus.com/pages/publications/84921507615

U2 - 10.1021/jm501307e

DO - 10.1021/jm501307e

M3 - Article (Academic Journal)

C2 - 25454499

AN - SCOPUS:84921507615

SN - 0022-2623

VL - 58

SP - 767

EP - 777

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

Shoemark DK , Williams C, Fahey MS, Watson JJ, Tyler SJ, Scoltock SJ et al. Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery. Journal of Medicinal Chemistry. 2015 Jan 22;58(2):767-777. Epub 2014 Dec 2. doi: 10.1021/jm501307e

Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery

Abstract

Research Groups and Themes

Keywords

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3-month Core Capability for Chemistry Research

Small molecule antagonists at the TrkA receptor for the treatment of pain

PUMP PRIMING RESEARCH TRANSLATIONAL INITIATIVE - SARTRE

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

Professor Matthew P Crump

Cite this

Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery

Abstract

Research Groups and Themes

Keywords

Access to Document

Handle.net

Other files and links

Embargoed Document

Fingerprint

Projects

3-month Core Capability for Chemistry Research

Small molecule antagonists at the TrkA receptor for the treatment of pain

PUMP PRIMING RESEARCH TRANSLATIONAL INITIATIVE - SARTRE

Equipment

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

Profiles

Professor Matthew P Crump

Cite this