4CRP

Solution structure of a TrkAIg2 domain construct for use in drug discovery

Summary for 4CRP

• Entry DOI: 10.2210/pdb4crp/pdb
• NMR Information: BMRB: 19824
• Descriptor: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR (1 entity in total)
• Functional Keywords: transferase, trkaig2, nmr construct, pain, alzheimers
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P04629
• Total number of polymer chains: 1
• Total formula weight: 11792.07

Authors

Shoemark, D.K.,Fahey, M.,Williams, C.,Sessions, R.B.,Crump, M.P.,Allen-Birt, S.J. (deposition date: 2014-02-28, release date: 2015-01-14, Last modification date: 2024-10-23)

Primary citation

Allen, S.J.,Watson, J.J.,Shoemark, D.K.,Barua, N.U.,Patel, N.K.
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., 58:767-, 2015

PubMed 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 signaling 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 (1)H-(15)N correlation spectra confirm that both NGF and a competing small molecule interact at the known binding interface in solution.

PubMed: 25454499
DOI: 10.1021/JM501307E

Experimental method

SOLUTION NMR