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gmn's KLHDC2 ligand design from Puzzle 2145.

KLHDC2 is shorthand for "Kelch domain-containing protein 2".

In Foldit, KLHDC2 is featured in a series of KLHDC2 ligand design puzzles. In these small molecule design puzzle puzzles, the goal is to design a small molecule (a ligand) which binds to the KLHDC2 protein.

The goals of the KLHDC2 puzzles are described in the Foldit blog post KLHDC2: New Small Molecule Design Puzzle Series.

A successful KLHDC2 ligand would be a PROTAC, or "proteolysis targeting chimera". The Foldit blog post PROTAC small molecule design project describes how PROTACs work with reference to the puzzles in the VHL ligand design series.

The KLHDC2 puzzles present only selected fragments of the actual KLHDC2 protein. The fragments form the "binding pocket" which will contain the ligand. Unlike most most Foldit puzzles, the protein part of the KLHDC2 puzzles is entirely locked, meaning the backbone and sidechains can't move or change.

The Kelch protein seen in the KLHDC2 puzzles. This protein is PDB 6D05, shown in Jmol with amino acid coloring.

A more complete KLHDC2 protein can be seen in PDB entries 6DO3, 6DO4, and 6DO5. These entries show the same KLHDC2 protein bound to different ligands.

The KLHDC2 protein in 6DO3, 6DO4, and 6D05 is a dimer, a protein composed of two identical chains, each with 363 segments. A protein of that size is considered to be "too large for Foldit".

The three KLHDC2 PDB entries are supported by the article Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase.

In Foldit, a test puzzle also featured a more complete protein with multiple Kelch domains. The devprev puzzle Drug Design Updates Test included 317 segments of a Kelch protein. Like the KLHDC2 ligand design puzzles, the test puzzle was a partial match for PDB ids 6DO3, 6DO4, and 6D05. Some of the gaps in coverage seem to be explained by "missing residues", amino acids that are known to be part of the protein, but can't be found in the X-ray crystallography results. The missing residues are presumably out there, but they can't be seen in the electron density "cloud".

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