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Architecture and hydration of the arginine‐binding site of neuropilin‐1
Author(s) -
Mota Filipa,
Fotinou Constantina,
Rana Rohini R.,
Chan A. W. Edith,
Yelland Tamas,
Arooz Mohamed T.,
O'Leary Andrew P.,
Hutton Jennie,
Frankel Paul,
Zachary Ian,
Selwood David,
Djordjevic Snezana
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14405
Subject(s) - neuropilin 1 , binding site , chemistry , neuropilin , ligand (biochemistry) , receptor tyrosine kinase , drug discovery , context (archaeology) , plasma protein binding , arginine , biophysics , biochemistry , stereochemistry , biology , receptor , amino acid , vegf receptors , vascular endothelial growth factor , cancer research , paleontology
Neuropilin‐1 ( NRP 1) is a transmembrane co‐receptor involved in binding interactions with variety of ligands and receptors, including receptor tyrosine kinases. Expression of NRP 1 in several cancers correlates with cancer stages and poor prognosis. Thus, NRP 1 has been considered a therapeutic target and is the focus of multiple drug discovery initiatives. Vascular endothelial growth factor ( VEGF ) binds to the b1 domain of NRP 1 through interactions between the C‐terminal arginine of VEGF and residues in the NRP 1‐binding site including Tyr297, Tyr353, Asp320, Ser346 and Thr349. We obtained several complexes of the synthetic ligands and the NRP 1‐b1 domain and used X‐ray crystallography and computational methods to analyse atomic details and hydration profile of this binding site. We observed side chain flexibility for Tyr297 and Asp320 in the six new high‐resolution crystal structures of arginine analogues bound to NRP 1. In addition, we identified conserved water molecules in binding site regions which can be targeted for drug design. The computational prediction of the VEGF ligand‐binding site hydration map of NRP 1 was in agreement with the experimentally derived, conserved hydration structure. Displacement of certain conserved water molecules by a ligand's functional groups may contribute to binding affinity, whilst other water molecules perform as protein–ligand bridges. Our report provides a comprehensive description of the binding site for the peptidic ligands’ C‐terminal arginines in the b1 domain of NRP 1, highlights the importance of conserved structural waters in drug design and validates the utility of the computational hydration map prediction method in the context of neuropilin. Database The structures were deposited to the PDB with accession numbers PDB ID : 5IJR , 5IYY , 5JHK , 5J1X , 5JGQ , 5JGI .