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Architecture and hydration of the arginine-binding site of neuropilin-1

DOI: 10.1111/febs.14405 DOI Help

Authors: Filipa Mota (Magnus Life Science) , Constantina Fotinou (Magnus Life Science) , Rohini Rhana (Magnus Life Science) , A. W. Edith Chan (University College London) , Tamas Yelland (Magnus Life Science) , Mohamed T. Arooz (University College London) , Andrew P. O'Leary (Magnus Life Science) , Jennie Hutton (Magnus Life Science) , Paul Frankel (Magnus Life Science; BHF Laboratories at University College London) , Ian Zachary (BHF Laboratories at University College London) , David Selwood (University College London) , Snezana Djordjevic (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Febs Journal

State: Published (Approved)
Published: February 2018
Diamond Proposal Number(s): 12305

Open Access Open Access

Abstract: Neuropilin-1 (NRP1) is a transmembrane co-receptor involved in binding interactions with variety of ligands and receptors, including receptor tyrosine kinases. Expression of NRP1 in several cancers correlates with cancer stages and poor prognosis. Thus, NRP1 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 NRP1 through interactions between the C-terminal arginine of VEGF and residues in the NRP1 binding site including Tyr297, Tyr353, Asp320, Ser346, and Thr349. We obtained several complexes of the synthetic ligands and the NRP1-b1 domain and used X-ray crystallography and computational methods to analyze atomic details and hydration profile of this binding site. We observed side chain flexibility for Tyr297 and Asp320 in the 6 new high resolution crystal structures of arginine analogues bound to NRP1. 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 NRP1 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 NRP1, 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.

Journal Keywords: x-ray crystallography; ligand-binding protein; vascular endothelial growth factor (VEGF); neuropilin; SPR

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 22/02/2018 14:24


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)