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Level: Advanced
Teaching Notes
Exploring a Protein Structure in the RCSB PDB: HIV-1 Protease
Learning Goals:
1. Visualize the structure of a given molecule using RCSB PDB resources.
2. Explore the structure to understand its structure function relationships
Educational Standards
A. Common Core
a. Craft and Structure
i. RI.9-10.4
ii. RI.11-12.4
b. Integration of Knowledge and Ideas
i. RI.9-10.7
ii. RI.11-12.7
B. Next Generation Science Standards
a. Practices
i. 8. Obtaining, Evaluating and Communicating Information
b. Crosscutting Concepts
i. 3. Scale, proportion and quantity
ii. 4. Systems and system models
iii. 6. Structure and function
c. Disciplinary Core Ideas
i. LS1.A: Structure and Function
ii. PS2.B: Types of Interactions
C. Advanced Placement Biology - Essential Knowledge (EK), Learning Objectives (LO),
Science Practices (SP)
a. EK 4.A.1
i. LO 4.2, SP 1.3
ii. LO 4.3, SP 6.1, 6.4
Teaching Notes:
About Protease:
The protease acts on the HIV polyprotein and cleaves it into smaller functional proteins
during maturation of the viral particle. If the protease activity is blocked the new viral particles
are unable to mature to form infectious virus hence blocking the spread of this infection. As a
result this has been an important target for drug development to treat HIV infection. Currently
HIV protease inhibitors form an important part of the combined antiretroviral treatment.
1. Structure:
a. The functional HIV Protease is composed of two identical protein chains that
interact symmetrically.
b. The active site of the enzyme is located in a tunnel formed by the two chains.
Developed as part of the RCSB Collaborative Curriculum Development Program 2015
Level: Advanced
Teaching Notes
Structure of the HIV-1 Protease, showing its different regions (PDB ID: 2hb4).
2. Function:
a. Access to the protease active site is through the flap region, which opens and
closes to let the substrate in.
HIV protease structure showing the opening and closing of the flap region. Open
flap: PDB ID 2pc0 and closed flap: PDB ID 2hb4
b. The active site consists of the triads, Asp25-Thr26-Gly27, conserved in each
monomer. The Asp 25 in both chains is the catalytic residue.
Developed as part of the RCSB Collaborative Curriculum Development Program 2015
Answers to Questions in Exercise:
Level: Advanced
Teaching Notes
Q1. How many polymer chains are there? What are they?
A1: There are 3 polymer chains as seen in the Chimera graphics window – chain A and B are the
protease chains, while chain C is that of an inhibitor, designed based on a substrate (of the
protease enzyme).
Q2. Describe how the polymer chains are organized in the structure? Based on this description
describe the function of HIV-1 Protease.
A2: The 2 chains of HIV-1 Protease form a dimer with a pocket in the middle of the interaction
interface between the 2 chains. The polymer chain C is bound to that pocket.
The HIV-1 protease functions as a dimer. The active sites of both the polymer chains are located
in the binding pocket where the inhibitor is bound. The polymer chain C closely resembles one of
the substrates of this enzyme.
Q3. A. Based on your explorations of the above selected amino acids and hydrogen bonds, list at
least 5 amino acids that are within hydrogen bonding distance of the atoms of chain C.
A3. A. The following amino acid side chains are H-bonded to the inhibitor
1. Asp 25 in chain A
2. Asp29 in chain A
3. Asp 30 in chain A
4. Asp 25 in chain B
5. Asp 29 in chain B (H-bond via water molecule)
Other amino acids in the vicinity include Ile 50 in chain A and Ala 28 in chain B
Q3.B. What type of amino acids are these. (Hint: think about the properties of the side chains of
these residues).
A3. B. Most of the closely interacting amino acids are all acidic (Aspartic acid/Aspartate)
Developed as part of the RCSB Collaborative Curriculum Development Program 2015