Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex

Andersen, Jacob Lauwring; Schrøder, Tenna Juul; Christensen, Søren; Strandbygård, Dorthe; Pallesen, Lone Tjener; García-Alai, María; Lindberg, Samsa; Langgård, Morten; Eskildsen, Jørgen; David, Laurent; Tagmose, Lena; Simonsen, Klaus B.; Maltas, Philip; Rønn, Lars Christian B.; Jong, Inge E.M. de; Malik, Ibrahim; Egebjerg, Jan; Karlsson, Jens-Jacob; Srinivas, U.; Sakumudi, Durga Rao; Eradi, Pradheep; Watson, Steven P.; Thirup, Søren

doi:10.1107/s1399004713030149

Cited by 32 publications

(26 citation statements)

References 43 publications

(41 reference statements)

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“…NT was found to bind within the tunnel of the b-propeller domain via its three C-terminal residues, YIL, 11 and we have recently shown that also small molecule inhibitors of NT binding occupies this YIL binding site. 12,13 Here we have set out to further study the structural properties of sortilin and the binding of NT using a broad biophysical approach. The data provided here suggest that NT is completely contained inside the tunnel of the b-propeller, firmly bound by its C-terminus in the previously reported binding site, and further attached by its N-terminal part at a low affinity site on the opposite side of the tunnel.…”

Section: Introductionmentioning

confidence: 99%

Revisiting the structure of the Vps10 domain of human sortilin and its interaction with neurotensin

et al. 2014

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Sortilin is a multifunctional receptor involved in sorting and apoptosis. We have previously reported a 2.0-Å structure of the Vps10 ectodomain in complex with one of its ligands, the tridecapeptide neurotensin. Here we set out to further characterize the structural properties of sortilin and its interaction with neurotensin. To this end, we have determined a new 2.7 Å structure using a crystal grown with a 10-fold increased concentration of neurotensin. Here a second peptide fragment was observed within the Vps10 b-propeller, which may in principle either represent a second molecule of neurotensin or the N-terminal part of the molecule bound at the previously identified binding site. However, in vitro binding experiments strongly favor the latter hypothesis. Neurotensin thus appears to bind with a 1:1 stoichiometry, and whereas the N-terminus does not bind on its own, it enhances the affinity in context of full-length neurotensin. We conclude that the N-terminus of neurotensin probably functions as an affinity enhancer for binding to sortilin by engaging the second binding site. Crystal packing differs partly from the previous structure, which may be due to variations in the degree and pattern of glycosylations. Consequently, a notable hydrophobic loop, not modeled previously, could now be traced. A computational analysis suggests that this and a neighboring loop may insert into the membrane and thus restrain movement of the Vps10 domain. We have, furthermore, mapped all N-linked glycosylations of CHO-expressed human sortilin by mass spectrometry and find that their locations are compatible with membrane insertion of the hydrophobic loops.

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Section: Introductionmentioning

confidence: 99%

Revisiting the structure of the Vps10 domain of human sortilin and its interaction with neurotensin

et al. 2014

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“…Neurotensin interacts with 3 neurotensin receptors (NTSRs): NTSR1, NTSR2, and NTSR3. Neurotensin-producing neurons are widespread in the brain and involved in several neuronal functions such as pain processing, blood pressure regulation, and food intake regulation (41). Outside the brain, neurotensin acts as a hormone with numerous endocrine and paracrine functions, such as regulation of intestinal motility, secretion of the pancreas, and tone of smooth vascular muscles (42).…”

Section: Neurotensin/ 177 Lu-3bp-227mentioning

confidence: 99%

Future of Theranostics: An Outlook on Precision Oncology in Nuclear Medicine

2019

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Molecular alterations in malignant disease result in the expression or upregulations of various targets that can be used for imaging and treatment with radiopharmaceuticals. This theranostic principle has acquired greater importance in personalized medicine in recent years, particularly in oncology, where advanced tumors can be treated effectively with low side effects. Since the pioneering use of 131 I in differentiated thyroid cancer in the 1940s, remarkable achievements in nuclear medicine endoradiotherapy have been demonstrated, mainly in the treatment of neuroendocrine neoplasms by using 177 Lulabeled somatostatin analogs or in the treatment of advanced prostate cancer using prostate-specific membrane antigen-directed radionuclide therapy. Besides that, this review focuses on promising novel radiopharmaceuticals and describes their preclinical and clinical status. Radiolabeled antibodies, such as 131 I-omburtamab directed against the B7-H3 protein on the surface of neuroblastoma cells; HuMab-5B1, a 89 Zr/ 177 Lu-labeled antibody for the treatment of CA19-9-expressing malignancies; and 177 Lu-lilotomab, a CD37 antibody for the treatment of B-cell lymphomas, are being highlighted. The neurotensin receptor ligand 111 In/ 177 Lu-3B-227 has demonstrated high potential in imaging and therapy for several malignancies (e.g., pancreatic adenocarcinomas). Targeting of the fibroblast activation protein is currently being explored for different tumor entities using PET imaging with the fibroblast activation protein inhibitor (FAPI) 68 Ga-FAPI-04, and the first therapeutic applications of 90 Y-FAPI-04 have been applied. After 2 decades of rapid development in theranostics, a variety of new targets are available for further clinical investigation.

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“…Neurotensin interagiert mit 3 Neurotensinrezeptoren, NTSR1, NTSR2 und NTSR3. NTSR1 und NTSR2 sind G-Protein gekoppelte Rezeptoren, die an der Zelloberfläche exprimiert sind, während NTSR3 zur Gruppe der "vacuolar protein sorting 10 protein" (Vps10 p)-Rezeptoren gehört, die eine wichtige Rolle im intrazellulären Transport verschiedener Proteine spielt [42].…”

Section: Neurotensin/ 177 Lu-3bp-227unclassified

“…Neurotensin und Neurotensinrezeptoren sind deshalb an einer ganzen Reihe neuronaler Funktionen wie Schmerzverarbeitung, Blutdruckregulation und Regulation der Nahrungsaufnahme beteiligt. Auch in der Pathophysiologie verschiedener neurologischer und psychiatrischer Erkrankungen wie Schizophrenie, M. Parkinson und Drogenabhängigkeit ist das Neurotensin-System involviert [42].…”

Section: Neurotensin/ 177 Lu-3bp-227unclassified

Neue Entwicklungen auf dem Gebiet der Theranostik

Weber

2019

Nuklearmediziner

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ZusammenfassungDiese Übersichtsarbeit stellt neue Radiopharmaka für die Tumordiagnostik und -therapie vor, die erfolgversprechende präklinische Ergebnisse gezeigt haben und aktuell in klinischen Studien untersucht werden. Dazu gehören mehrere radioaktiv markierte Antikörper wie 131I-Omburtamab, ein gegen das B7-H3-Protein gerichteter Antikörper, der zur Therapie von Neuroblastomen eingesetzt wird; HuMab-5B1, ein 89Zr/177Lu markierter Antikörper zur Therapie von CA19-9 exprimierenden Tumoren und 177Lu-Lilotomab, ein Antikörper gegen das Oberflächenantigen CD37 für die Therapie von B-Zell-Lymphomen. Weitere Beispiele sind der Neurotensin Rezeptor Ligand 111In/177Lu-3B-227 für die Diagnostik und Therapie von verschiedenen Tumorerkrankungen, insbesondere Adenokarzinomen des Pankreas und der Phospholipidether 131I/124I-CLR1404, der wahrscheinlich aufgrund einer veränderten Membranstruktur in verschiedenen Tumorzelltypen angereichert wird. Neben diesen, von Tumorzellen exprimierten Zielstrukturen wird auch das Fibroblasten Aktivierungs Protein (FAP), das im Tumorstroma gebildet wird, als Zielstruktur für die Bildgebung und Therapie eingesetzt (68Ga/90Y-FAPI-04). Diese neuen Radiopharmaka haben das Potenzial für die Therapie einer ganzen Reihe von Tumorerkrankungen und ihre Effektivität sollte in systematischen Studien untersucht werden.

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Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex

Abstract: The identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex are reported.

Cited by 32 publications

References 43 publications

Revisiting the structure of the Vps10 domain of human sortilin and its interaction with neurotensin

Revisiting the structure of the Vps10 domain of human sortilin and its interaction with neurotensin

Future of Theranostics: An Outlook on Precision Oncology in Nuclear Medicine

Neue Entwicklungen auf dem Gebiet der Theranostik

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