Interactions of the male contraceptive target EPPIN with semenogelin-1 and small organic ligands
© 2023. Springer Nature Limited..
Novel male contraceptives will promote gender equality in sharing contraceptive responsibility. The sperm-associated protein epididymal protease inhibitor (EPPIN) is a promising target for non-hormonal male contraception. EPPIN interacts with the semen coagulum protein semenogelin-1 (SEMG1) on the sperm surface, leading to transient inhibition of sperm motility after ejaculation. Small organic molecules targeting EPPIN's SEMG1-binding are under development as male contraceptives. Here, we combined computational approaches to uncover key aspects underlying EPPIN binding to SEMG1 and small organic ligands. We generated a human EPPIN model showing a typical arrangement of the WFDC (Whey-acid four disulfide core)-type and Kunitz-type domains, connected by a hinge region. Determining the EPPIN model's intrinsic motion by molecular dynamics simulations and normal mode analysis revealed a conformation, presenting a binding pocket that accommodates SEMG1Glu229-Gln247, EP055, and EP012. EPPIN's residues Phe63 and Lys68 (WFDC domain), Asp71 (hinge region), and Asn113, Asn114, and Asn115 (Kunitz domain) were identified as hot spots for SEMG1, EP055, and EP012 binding. Moreover, hydrophobic and hydrophilic residues in the WFDC and Kunitz domains allow plasma membrane anchoring, orienting the EPPIN binding pocket to the solvent. Targeting EPPIN's essential residues for its biomolecular interactions may improve the rational design of EPPIN ligands as spermiostatic compounds.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Scientific reports - 13(2023), 1 vom: 01. Sept., Seite 14382 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Gomes, Antoniel A S [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Contraceptive Agents |
|---|
| Anmerkungen: |
Date Completed 04.09.2023 Date Revised 21.11.2023 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41598-023-41365-1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36155821X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36155821X | ||
| 003 | DE-627 | ||
| 005 | 20231226210835.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41598-023-41365-1 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1205.xml |
| 035 | |a (DE-627)NLM36155821X | ||
| 035 | |a (NLM)37658081 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Gomes, Antoniel A S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Interactions of the male contraceptive target EPPIN with semenogelin-1 and small organic ligands |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 04.09.2023 | ||
| 500 | |a Date Revised 21.11.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. Springer Nature Limited. | ||
| 520 | |a Novel male contraceptives will promote gender equality in sharing contraceptive responsibility. The sperm-associated protein epididymal protease inhibitor (EPPIN) is a promising target for non-hormonal male contraception. EPPIN interacts with the semen coagulum protein semenogelin-1 (SEMG1) on the sperm surface, leading to transient inhibition of sperm motility after ejaculation. Small organic molecules targeting EPPIN's SEMG1-binding are under development as male contraceptives. Here, we combined computational approaches to uncover key aspects underlying EPPIN binding to SEMG1 and small organic ligands. We generated a human EPPIN model showing a typical arrangement of the WFDC (Whey-acid four disulfide core)-type and Kunitz-type domains, connected by a hinge region. Determining the EPPIN model's intrinsic motion by molecular dynamics simulations and normal mode analysis revealed a conformation, presenting a binding pocket that accommodates SEMG1Glu229-Gln247, EP055, and EP012. EPPIN's residues Phe63 and Lys68 (WFDC domain), Asp71 (hinge region), and Asn113, Asn114, and Asn115 (Kunitz domain) were identified as hot spots for SEMG1, EP055, and EP012 binding. Moreover, hydrophobic and hydrophilic residues in the WFDC and Kunitz domains allow plasma membrane anchoring, orienting the EPPIN binding pocket to the solvent. Targeting EPPIN's essential residues for its biomolecular interactions may improve the rational design of EPPIN ligands as spermiostatic compounds | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Contraceptive Agents, Male |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Contraceptive Agents |2 NLM | |
| 700 | 1 | |a Santos, Natália C M |e verfasserin |4 aut | |
| 700 | 1 | |a Rosa, Leonardo R |e verfasserin |4 aut | |
| 700 | 1 | |a Borges, Rafael J |e verfasserin |4 aut | |
| 700 | 1 | |a Fontes, Marcos R M |e verfasserin |4 aut | |
| 700 | 1 | |a Hamil, Katherine G |e verfasserin |4 aut | |
| 700 | 1 | |a O'Rand, Michael G |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, Erick J R |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Scientific reports |d 2011 |g 13(2023), 1 vom: 01. Sept., Seite 14382 |w (DE-627)NLM215703936 |x 2045-2322 |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2023 |g number:1 |g day:01 |g month:09 |g pages:14382 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41598-023-41365-1 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2023 |e 1 |b 01 |c 09 |h 14382 | ||