High resolution crystal structure of substrate-free human neprilysin

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Abstract

Neprilysin is a transmembrane M13 zinc metalloprotease responsible for the degradation of several biologically active peptides including insulin, enkephalin, substance P, bradykinin, endothelin-1, neurotensin and amyloid-β. The protein has received attention for its role in modulating blood pressure responses with its inhibition producing an antihypertensive response. To date, several inhibitor bound crystal structures of the human neprilysin extracellular domain have been determined, but, a structure free of bound inhibitor or substrate has yet to be reported. Here, we report the first crystal structure free of substrate or inhibitor for the extracellular catalytic domain of human neprilysin at 1.9 Å resolution. This structure will provide a reference point for comparisons to future inhibitor or substrate bound structures. The neprilysin structure also reveals that a closed protein conformation can be adopted in protein crystals absent of bound substrate or inhibitor.

LanguageEnglish
JournalJournal of Structural Biology
Early online date12 Jun 2018
DOIs
StatusE-pub ahead of print - 12 Jun 2018

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Neprilysin
Neurotensin
Protein Conformation
Enkephalins
Metalloproteases
Bradykinin
Endothelin-1
Substance P
Amyloid
Antihypertensive Agents
Zinc
Catalytic Domain
Proteins
Insulin
Blood Pressure
Peptides

Cite this

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title = "High resolution crystal structure of substrate-free human neprilysin",
abstract = "Neprilysin is a transmembrane M13 zinc metalloprotease responsible for the degradation of several biologically active peptides including insulin, enkephalin, substance P, bradykinin, endothelin-1, neurotensin and amyloid-β. The protein has received attention for its role in modulating blood pressure responses with its inhibition producing an antihypertensive response. To date, several inhibitor bound crystal structures of the human neprilysin extracellular domain have been determined, but, a structure free of bound inhibitor or substrate has yet to be reported. Here, we report the first crystal structure free of substrate or inhibitor for the extracellular catalytic domain of human neprilysin at 1.9 {\AA} resolution. This structure will provide a reference point for comparisons to future inhibitor or substrate bound structures. The neprilysin structure also reveals that a closed protein conformation can be adopted in protein crystals absent of bound substrate or inhibitor.",
author = "Stephen Moss and Vasanta Subramanian and Acharya, {K Ravi}",
note = "Copyright {\circledC} 2018. Published by Elsevier Inc.",
year = "2018",
month = "6",
day = "12",
doi = "10.1016/j.jsb.2018.06.004",
language = "English",
journal = "Journal of Structural Biology",
issn = "1047-8477",
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T1 - High resolution crystal structure of substrate-free human neprilysin

AU - Moss, Stephen

AU - Subramanian, Vasanta

AU - Acharya, K Ravi

N1 - Copyright © 2018. Published by Elsevier Inc.

PY - 2018/6/12

Y1 - 2018/6/12

N2 - Neprilysin is a transmembrane M13 zinc metalloprotease responsible for the degradation of several biologically active peptides including insulin, enkephalin, substance P, bradykinin, endothelin-1, neurotensin and amyloid-β. The protein has received attention for its role in modulating blood pressure responses with its inhibition producing an antihypertensive response. To date, several inhibitor bound crystal structures of the human neprilysin extracellular domain have been determined, but, a structure free of bound inhibitor or substrate has yet to be reported. Here, we report the first crystal structure free of substrate or inhibitor for the extracellular catalytic domain of human neprilysin at 1.9 Å resolution. This structure will provide a reference point for comparisons to future inhibitor or substrate bound structures. The neprilysin structure also reveals that a closed protein conformation can be adopted in protein crystals absent of bound substrate or inhibitor.

AB - Neprilysin is a transmembrane M13 zinc metalloprotease responsible for the degradation of several biologically active peptides including insulin, enkephalin, substance P, bradykinin, endothelin-1, neurotensin and amyloid-β. The protein has received attention for its role in modulating blood pressure responses with its inhibition producing an antihypertensive response. To date, several inhibitor bound crystal structures of the human neprilysin extracellular domain have been determined, but, a structure free of bound inhibitor or substrate has yet to be reported. Here, we report the first crystal structure free of substrate or inhibitor for the extracellular catalytic domain of human neprilysin at 1.9 Å resolution. This structure will provide a reference point for comparisons to future inhibitor or substrate bound structures. The neprilysin structure also reveals that a closed protein conformation can be adopted in protein crystals absent of bound substrate or inhibitor.

U2 - 10.1016/j.jsb.2018.06.004

DO - 10.1016/j.jsb.2018.06.004

M3 - Article

JO - Journal of Structural Biology

T2 - Journal of Structural Biology

JF - Journal of Structural Biology

SN - 1047-8477

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