Publication detail

Targeting Neuroblastoma Cell Surface Proteins: Recommendations for Homology Modeling of hNET, ALK, and TrkB

HADDAD, Y. HEGER, Z. ADAM, V.

Original Title

Targeting Neuroblastoma Cell Surface Proteins: Recommendations for Homology Modeling of hNET, ALK, and TrkB

Type

journal article in Web of Science

Language

English

Original Abstract

Targeted therapy is a promising approach for treatment of neuroblastoma as evident from the large number of targeting agents employed in clinical practice today. In the absence of known crystal structures, researchers rely on homology modeling to construct template-based theoretical structures for drug design and testing. Here, we discuss three candidate cell surface proteins that are suitable for homology modeling: human norepinephrine transporter (hNET), anaplastic lymphoma kinase (ALK), and neurotrophic tyrosine kinase receptor 2 (NTRK2 or TrkB). When choosing templates, both sequence identity and structure quality are important for homology modeling and pose the first of many challenges in the modeling process. Homology modeling of hNET can be improved using template models of dopamine and serotonin transporters instead of the leucine transporter (LeuT). The extracellular domains of ALK and TrkB are yet to be exploited by homology modeling. There are several idiosyncrasies that require direct attention throughout the process of model construction, evaluation and refinement. Shifts/gaps in the alignment between the template and target, backbone outliers and side-chain rotamer outliers are among the main sources of physical errors in the structures. Low-conserved regions can be refined with loop modeling method. Residue hydrophobicity, accessibility to bound metals or glycosylation can aid in model refinement. We recommend resolving these idiosyncrasies as part of “good modeling practice” to obtain highest quality model. Decreasing physical errors in protein structures plays major role in the development of targeting agents and understanding of chemical interactions at the molecular level.

Keywords

neuroblastoma; targeted therapy; homology modeling; norepinephrine transporter; anaplastic lymphoma kinase; neurotrophic tyrosine kinase receptor

Authors

HADDAD, Y.; HEGER, Z.; ADAM, V.

Released

20. 1. 2017

Publisher

Frontiers

ISBN

1662-5099

Periodical

Frontiers in Molecular Neuroscience

Year of study

10

Number

7

State

Swiss Confederation

Pages from

1

Pages to

7

Pages count

7

URL

http://journal.frontiersin.org/article/10.3389/fnmol.2017.00007/full

Full text in the Digital Library

http://hdl.handle.net/11012/69379

BibTex

@article{BUT134300,
  author="Yazan Abdulmajeed Eyadh {Haddad} and Zbyněk {Heger} and Vojtěch {Adam}",
  title="Targeting Neuroblastoma Cell Surface Proteins: Recommendations for Homology Modeling of hNET, ALK, and TrkB",
  journal="Frontiers in Molecular Neuroscience",
  year="2017",
  volume="10",
  number="7",
  pages="1--7",
  doi="10.3389/fnmol.2017.00007",
  issn="1662-5099",
  url="http://journal.frontiersin.org/article/10.3389/fnmol.2017.00007/full"
}