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Background <p>Human growth differentiation factor 5 (GDF5) is a member of the bone morphogenic protein family and plays many critical roles in chondrogenic development and child growth. The mature GDF5 exists in a homodimer form that is traditionally considered to possess a conformational wrist epitope in monomers 1/2 and a linear knuckle epitope in monomer 2, responsible for the recognition and binding of its cognate type-I and type-II receptors, respectively.</p> Methods <p>By systematically examining the co-crystallized complex structure of GDF5 with its cognate repulsive guidance molecule-A (RGMA) suppressor at structural, energetic and dynamic levels, we herein suggest an additional shoulder epitope as the specific recognition site of this suppressor partner, which is a linear epitope located in GDF5 monomer 1 and natively structured into a helical hairpin conformation in GDF5 protein context. Shoulder is partially overlapped with wrist but fully independent of knuckle, implicating that the RGMA suppressor can competitively disrupt type-I receptor signaling by sharing a common binding site for them.</p> Findings <p>A linear LEP peptide is derived from the shoulder sequence region, which, however, is intrinsically disordered and cannot maintain in the native helical hairpin conformation, thus unable to bind RGMA effectively. Instead, two cyclic peptides LEPc1 and LEPc2 are rationally designed from the LEP by introducing a disulfide bridge across the two arms of helical hairpin, which are expected to stabilize the native hairpin and to reduce the peptide flexibility. Computational modeling and experimental assay reveal that the peptide affinity to RGMA is improved moderately and considerably by 2.5-fold and 7.7-fold upon the LEPc1 and LEPc2 disulfide-bridging cyclizations, respectively. </p> Conclusion <p>We therefore expect the shoulder-derived cyclic peptides can be exploited as lead entities for further developing therapeutic peptidic agents to target the GDF5–RGMA interaction in a self-competitive manner.</p> Graphical Abstract <p></p>

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Sequence Narrowing and Structural Mapping of Human Growth Differentiation Factor-5 (GDF5) Shoulder Epitope into a Continuous Helical Hairpin Window as Its Suppressor Recognition Site

  • 期刊论文

  • 发表日期：

    2026年6月2日

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  • Junli Ren,
  • Yuanyuan Yang

摘要

Background

Human growth differentiation factor 5 (GDF5) is a member of the bone morphogenic protein family and plays many critical roles in chondrogenic development and child growth. The mature GDF5 exists in a homodimer form that is traditionally considered to possess a conformational wrist epitope in monomers 1/2 and a linear knuckle epitope in monomer 2, responsible for the recognition and binding of its cognate type-I and type-II receptors, respectively.

Methods

By systematically examining the co-crystallized complex structure of GDF5 with its cognate repulsive guidance molecule-A (RGMA) suppressor at structural, energetic and dynamic levels, we herein suggest an additional shoulder epitope as the specific recognition site of this suppressor partner, which is a linear epitope located in GDF5 monomer 1 and natively structured into a helical hairpin conformation in GDF5 protein context. Shoulder is partially overlapped with wrist but fully independent of knuckle, implicating that the RGMA suppressor can competitively disrupt type-I receptor signaling by sharing a common binding site for them.

Findings

A linear LEP peptide is derived from the shoulder sequence region, which, however, is intrinsically disordered and cannot maintain in the native helical hairpin conformation, thus unable to bind RGMA effectively. Instead, two cyclic peptides LEPc1 and LEPc2 are rationally designed from the LEP by introducing a disulfide bridge across the two arms of helical hairpin, which are expected to stabilize the native hairpin and to reduce the peptide flexibility. Computational modeling and experimental assay reveal that the peptide affinity to RGMA is improved moderately and considerably by 2.5-fold and 7.7-fold upon the LEPc1 and LEPc2 disulfide-bridging cyclizations, respectively.

Conclusion

We therefore expect the shoulder-derived cyclic peptides can be exploited as lead entities for further developing therapeutic peptidic agents to target the GDF5–RGMA interaction in a self-competitive manner.

Graphical Abstract