[NMR paper] 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.
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.
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.
J Med Chem. 2014 Dec 2;
Authors: Shoemark DK, Williams C, Fahey MS, Watson JJ, Tyler SJ, Scoltock SJ, Ellis RZ, Wickenden E, Burton AJ, Hemmings JL, Bailey CD, Dawbarn D, Jane DE, Willis CL, Sessions RB, Allen SJ, Crump MP
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 ?-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 (1)H-(15)N correlation spectra confirm that both NGF and a competing small molecule, interact at the known binding interface in solution.
PMID: 25454499 [PubMed - as supplied by publisher]
[NMR paper] High-Quality NMR Structure of Human Anti-Apoptotic Protein Domain Mcl-1(171-327) for Cancer Drug Design.
High-Quality NMR Structure of Human Anti-Apoptotic Protein Domain Mcl-1(171-327) for Cancer Drug Design.
Related Articles High-Quality NMR Structure of Human Anti-Apoptotic Protein Domain Mcl-1(171-327) for Cancer Drug Design.
PLoS One. 2014;9(5):e96521
Authors: Liu G, Poppe L, Aoki K, Yamane H, Lewis J, Szyperski T
Abstract
A high-quality NMR solution structure is presented for protein hMcl-1(171-327) which comprises residues 171-327 of the human anti-apoptotic protein Mcl-1 (hMcl-1). Since this construct contains the three...
nmrlearner
Journal club
0
05-03-2014 10:42 PM
[NMR paper] NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors.
NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors.
Related Articles NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors.
Proc Natl Acad Sci U S A. 2013 Nov 4;
Authors: Skora L, Mestan J, Fabbro D, Jahnke W, Grzesiek S
Abstract
Successful treatment of chronic myelogenous leukemia is based on inhibitors binding to the ATP site of the deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl)...
nmrlearner
Journal club
0
11-06-2013 10:20 PM
New Protein Evolution Insight Could Improve Drug Design - Drug Discovery & Development
<img alt="" height="1" width="1" />
New Protein Evolution Insight Could Improve Drug Design
Drug Discovery & Development
The team used a variety of techniques to characterize the two versions of the enzyme, including X-ray crystallography and nuclear magnetic resonance, analyses of DHFR amino-acid sequences and evaluations of the enzyme's functionality in cells and in ...
and more »
New Protein Evolution Insight Could Improve Drug Design - Drug Discovery & Development
More...
nmrlearner
Online News
0
10-01-2013 09:43 AM
[NMR paper] Novel inhibitor binding site discovery on HIV-1 capsid N-terminal domain by NMR and X-ray crystallography.
Novel inhibitor binding site discovery on HIV-1 capsid N-terminal domain by NMR and X-ray crystallography.
Related Articles Novel inhibitor binding site discovery on HIV-1 capsid N-terminal domain by NMR and X-ray crystallography.
ACS Chem Biol. 2013 Mar 15;
Authors: Goudreau N, Lemke CT, Faucher AM, Grand-Maître C, Goulet S, Lacoste JE, Rancourt J, Malenfant E, Mercier JF, Titolo S, Mason SW
Abstract
The HIV-1 capsid (CA) protein, a domain of Gag, which participates in formation of both the mature and immature capsid, represents a...
nmrlearner
Journal club
0
03-19-2013 01:22 PM
[NMR paper] NMR backbone assignments of the tyrosine kinase domain of human fibroblast growth factor receptor 1.
NMR backbone assignments of the tyrosine kinase domain of human fibroblast growth factor receptor 1.
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--production.springer.de-OnlineResources-Logos-springerlink.gif Related Articles NMR backbone assignments of the tyrosine kinase domain of human fibroblast growth factor receptor 1.
Biomol NMR Assign. 2013 Jan 17;
Authors: Vajpai N, Schott AK, Vogtherr M, Breeze AL
Abstract
Members of the fibroblast growth factor receptor tyrosine kinase family (FGFR1-4) play an important role in many...
nmrlearner
Journal club
0
02-03-2013 10:19 AM
[NMR paper] NMR spectroscopy and protein structure determination: applications to drug discovery
NMR spectroscopy and protein structure determination: applications to drug discovery and development.
Related Articles NMR spectroscopy and protein structure determination: applications to drug discovery and development.
Curr Pharm Biotechnol. 2005 Apr;6(2):105-20
Authors: Wishart D
Recent technological advances in NMR methods and instrumentation are having a significant impact in structural biology. These innovations are also impacting pharmaceutical biotechnology as it is now possible to use NMR spectroscopy to rapidly characterize a growing...
nmrlearner
Journal club
0
11-25-2010 08:21 PM
[NMR paper] NMR structure and peptide hormone binding site of the first extracellular domain of a
NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor.
Related Articles NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor.
Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12836-41
Authors: Grace CR, Perrin MH, DiGruccio MR, Miller CL, Rivier JE, Vale WW, Riek R
The corticotropin-releasing factor (CRF) ligand family has diverse effects on the CNS, including the modulation of the stress response. The ligands'...
nmrlearner
Journal club
0
11-24-2010 10:01 PM
[NMR paper] 1.67-A X-ray structure of the B2 immunoglobulin-binding domain of streptococcal prote
1.67-A X-ray structure of the B2 immunoglobulin-binding domain of streptococcal protein G and comparison to the NMR structure of the B1 domain.
Related Articles 1.67-A X-ray structure of the B2 immunoglobulin-binding domain of streptococcal protein G and comparison to the NMR structure of the B1 domain.
Biochemistry. 1992 Nov 3;31(43):10449-57
Authors: Achari A, Hale SP, Howard AJ, Clore GM, Gronenborn AM, Hardman KD, Whitlow M
The structure of the B2 immunoglobulin-binding domain of streptococcal protein G has been determined at 1.67-A...
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.
Linear Mode
